Kinase Inhibitors Useful For The Treatment Of Proliferative Diseases

ABSTRACT

The present invention relates to novel kinase inhibitors and modulator compounds useful for the treatment of various diseases. More particularly, the invention is concerned with such compounds, kinase/compound adducts, methods of treating diseases, and methods of synthesis of the compounds. Preferrably, the compounds are useful for the modulation of kinase activity of Raf kinases and disease polymorphs thereof. Compounds of the present invention find utility in the treatment of mammalian cancers and especially human cancers including but not limited to malignant melanoma, colorectal cancer, ovarian cancer, papillary thyroid carcinoma, non small cell lung cancer, and mesothelioma. Compounds of the present invention also find utility in the treatment of rheumatoid arthritis and retinopathies including diabetic retinal neuropathy and macular degeneration.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of Provisional Application60/844,552 filed Sep. 14, 2006. This application is incorporated byreference herein.

FIELD OF THE INVENTION

The present invention relates to novel kinase inhibitors and modulatorcompounds useful for the treatment of various diseases. Moreparticularly, the invention is concerned with such compounds, methods oftreating diseases, and methods of synthesis of the compounds.Preferrably, the compounds are useful for the modulation of kinaseactivity of Raf kinases and disease polymorphs thereof.

BACKGROUND OF THE INVENTION

Several members of the protein kinase family have been clearlyimplicated in the pathogenesis of various proliferative diseases andthus represent important targets for treatment of these diseases. Someof the proliferative diseases relevant to this invention include cancer,rheumatoid arthritis, atherosclerosis, and retinopathies. Importantexamples of kinases which have been shown to cause or contribute to thepathogensis of these diseases including, but not limited to, are BRaf,CRaf, Abl, KDR(VEGF), EGFR/HER1, HER2, HER3, cMET, FLT-3, PDGFR-a,PDGFR-b, p38, eKIT, and JAK2.

A major signaling pathway downstream of cell surface growth factorreceptor activation is the Ras-RAF-MEK-ERK-MAP kinase pathway(Peyssonnaux, C. et al, Biol. Cell (2001) 93: 53-62, Cancers arise whenmutations occur in one or more of the proteins involved in thissignaling cascade. Cell proliferation and differentiation becomedysregulated and cell survival mechanisms are activated which allowunregulated cancer cells to override protective programmed cell deathsurveillance. Mutations in the p21-Ras protein have been shown to be amajor cause of dysregulation of this signaling pathway, leading to thedevelopment of human cancers. P21-Ras mutations have been identified inapproximately 30% of human cancers (Bolton et al, Ann. Rep. Med. Chem.(1994) 29: 165-174). Cancer-causing mutations in the P21-Ras proteinlead to a constituitively active signaling cascade, causing unregulatedactivation of the downstream components of the RAF-MEK-ERK-MAP kinasepathway (Magnuson et al., Semin. Cancer Biol. (1994) δ: 247-253). Thethree RAF kinases which participate in this signaling cascade are knownas ARAF, BRAF, and CRAF (Peyssonnaux, C. et al, Biol. Cell (2001) 93:53-62; Avruch, J., Recent Prog. Harm. Res. (2001) 56: 127-155; Kolch,W., Biochem. J. (2000) 351: 289-305). These RAF kinase isoforms are allactivated by Ras, and thus are activated in cancers that result frommutated and upregulated p21-Ras protein activity. In addition toactivation of this signaling cascade at the initial p21-Ras proteinlevel, mutations have also been found in BRAF kinase which results inactivation of the cascade downstream from p21-Ras (Davies, H., et al,Nature (2002) 417: 949-954). A dominant single site mutation at position600 in the BRAF kinase was shown to be particularly aggressive andlinked to approximately 80% of the observed human malignant melanomas.This mutation substitutes the negatively charged amino acid glutamicacid for the normally occurring neutral amino acid valine. This singlesite mutation is sufficient to render the mutated BRAF kinaseconstituitively active, resulting in signaling pathway dysregulation andhuman cancer. Hence small molecule inhibitors of BRAF kinase are arational approach to the treatment of human malignancy, whether thesignaling mutation is at the level of the upstream p21-Ras protein or atthe level of BRAF kinase.

The majority of small molecule kinase inhibitors that have been reportedhave been shown to bind in one of three ways. Most of the reportedinhibitors interact with the ATP binding domain of the active site andexert their effects by competing with ATP for occupancy. Otherinhibitors have been shown to bind to a separate hydrophobic region ofthe protein known as the “DFG-in-conformation” pocket, and still othershave been shown to bind to both the ATP domain and the“DFG-in-conformation” pocket. Examples specific to inhibitors of RAFkinases can be found in Lowinger et al, Current Pharmaceutical Design(2002) 8: 2269-2278; Dumas, J. et al., Current Opinion in Drug Discovery& Development (2004) 7: 600-616; Dumas, J. et al, WO 2003068223 A1(2003); Dumas, J., et al, WO 9932455 A1 (1999), and Wan, P. T. C., etal, Cell (2004) 116: 855-867.

Physiologically, kinases are regulated by a commonactivation/deactivation mechanism wherein a specific activation loopsequence of the kinase protein binds into a specific pocket on the sameprotein which is referred to as the switch control pocket (see WO200380110049 for further details). Such binding occurs when specificamino acid residues of the activation loop are modified for example byphosphorylation, oxidation, or nitrosylation. The binding of theactivation loop into the switch pocket results in a conformationalchange of the protein into its active form (Huse, M. and Kuriyan, J.Cell (109) 275-282.)

SUMMARY OF THE INVENTION

Compounds of the present invention find utility in the treatment ofmammalian cancers and especially human cancers including but not limitedto malignant melanoma, colorectal cancer, ovarian cancer, papillarythyroid carcinoma, lung cancers, kidney cancers, pancreatic cancer,glioblastomas, myeloproliferative diseases, and mesothelioma. Compoundsof the present invention also find utility in the treatment ofinflammatory diseases including rheumatoid arthritis, retinopathiesincluding diabetic retinal neuropathy and macular degeneration,cardiovascular disease and metabolic diseases.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following descriptions refer to various compounds and moietiesthereof.

Carbocyclyl refers to carbon rings taken from cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl,norborenyl, bicyclo[2.2.2]octanyl, and bicyclo[2.2.2]octenyl;Halogen refers to fluorine, chlorine, bromine and iodine;Aryl refers to monocyclic or fused bicyclic ring systems characterizedby delocalized π electrons (aromaticity) shared among the ring carbonatoms of at least one carbocyclic ring; preferred aryl rings are takenfrom phenyl, naphthyl, tetrahydronaphthyl, indenyl, and indanyl;Heteroaryl refers to monocyclic or fused bicyclic ring systemscharacterized by delocalized electrons (aromaticity) shared among thering carbon or heteroatoms including nitrogen, oxygen, or sulfur of atleast one carbocyclic or heterocyclic ring; heteroaryl rings are takenfrom, but not limited to, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl,isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazinyl, indolyl, indolinyl, isoindolyl, isoindolinyl,indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl,benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl,benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl,pyrazolopyridinyl, imidazolonopyridinyl, thiazolopyridinyl,thiazolonopyridinyl, oxazolopyridinyl, oxazolonopyridinyl,isoxazolopyridinyl, isothiazolopyridinyl, triazolopyridinyl,imidazopyrimidinyl, pyrazolopyrimidinyl, imidazolonopyrimidinyl,thiazolopyridiminyl, thiazolonopyrimidinyl, oxazolopyridiminyl,oxazolonopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyl,triazolopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl,pyrazolopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl,pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl,quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl,benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl,tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl,benzoazepinyl, benzodiazepinyl, benzoxapinyl, or benzoxazepinyl;Heterocyclyl refers to monocyclic rings containing carbon andheteroatoms taken from oxygen, nitrogen, or sulfur and wherein there isnot delocalized π electrons (aromaticity) shared among the ring carbonor heteroatoms; heterocyclyl rings include, but are not limited to,oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl,oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl,tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl,thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide,piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl;Poly-aryl refers to two or more monocyclic or fused aryl bicyclic ringsystems characterized by delocalized π electrons (aromaticity) sharedamong the ring carbon atoms of at least one carbocyclic ring wherein therings contained therein are optionally linked together;Poly-heteroaryl refers to two or more monocyclic or fused bicyclicsystems characterized by delocalized π electrons (aromaticity) sharedamong the ring carbon or heteroatoms including nitrogen, oxygen, orsulfur of at least one carbocyclic or heterocyclic ring wherein therings contained therein are optionally linked together, wherein at leastone of the monocyclic or fused bicyclic rings of the poly-heteroarylsystem is taken from heteroaryl as defined broadly above and the otherrings are taken from either aryl, heteroaryl, or heterocyclyl as definedbroadly above;Poly-heterocyclyl refers to two or more monocyclic or fused bicyclicring systems containing carbon and heteroatoms taken from oxygen,nitrogen, or sulfur and wherein there is not delocalized π electrons(aromaticity) shared among the ring carbon or heteroatoms wherein therings contained therein are optionally linked, wherein at least one ofthe monocyclic or fused bicyclic rings of the poly-heteroaryl system istaken from heterocyclyl as defined broadly above and the other rings aretaken from either aryl, heteroaryl, or heterocyclyl as defined broadlyabove;Lower alkyl refers to straight or branched chain C1-C6alkyls;

Substituted in connection with a moiety refers to the fact that afurther substituent may be attached to the moiety to any acceptablelocation on the moiety.

The term salts embraces pharmaceutically acceptable salts commonly usedto form alkali metal salts of free acids and to form addition salts offree bases. The nature of the salt is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable acidaddition salts may be prepared from an inorganic acid or from an organicacid. Examples of such inorganic acids are hydrochloric, hydrobromic,hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriateorganic acids may be selected from aliphatic, cycloaliphatic, aromatic,arylaliphatic, and heterocyclyl containing carboxylic acids and sulfonicacids, examples of which are formic, acetic, propionic, succinic,glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, stearic, salkylic, p-hydroxybenzoic, phenylacetic,mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic,2-hydroxyethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic,2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic,3-hydroxybutyric, galactaric and galacturonic acid. Suitablepharmaceutically-acceptable salts of free acid-containing compounds ofthe invention include metallic salts and organic salts. More preferredmetallic salts include, but are not limited to appropriate alkali metal(group Ia) salts, alkaline earth metal (group IIa) salts and otherphysiological acceptable metals. Such salts can be made from aluminum,calcium, lithium, magnesium, potassium, sodium and zinc. Preferredorganic salts can be made from primary amines, secondary amines,tertiary amines and quaternary ammonium salts, including in part,tromethamine, diethylamine, tetra-N-methylammonium,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine.

The term prodrug refers to derivatives of active compounds which revertin vivo into the active form. For example, a carboxylic acid form of anactive drug may be esterified to create a prodrug, and the ester issubsequently converted in vivo to revert to the carboxylic acid form.See Ettmayer et. al, J. Med. Chem., 2004, 47(10), 2393-2404 and Lorenziet. al, J. Pharm. Exp. Therapeutics, 2005, 883-8900 for reviews.

1. First Aspect of the Invention—Compounds, Preparations and Methods

In the first aspect of the invention, compounds are of the formula Ia

wherein X—Y in order is C═N or N—CH2;wherein E1 is selected from the group consisting cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl,thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl,pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl,pyrimidinyl and naphthyl;

wherein A is selected from the group consisting of phenyl, naphthyl,C3-C8-carbocyclyl, indanyl, tetralinyl, indanyl, G1, G2, G3, G4 and—CHR4R8;

G1 is a heteroaryl taken from the group consisting of pyrrolyl, furyl,thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl,pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl,pyridazinyl, triazinyl, pyridinyl, and pyrimidinyl;G2 is a fused bicyclic heteroaryl taken from the group consisting ofindolyl, indolinyl, isoindolyl, isoindolinyl, indazolyl, benzofuranyl,benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl,benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl,benzimidazolonyl, benztriazolyl, imidazopyridinyl, pyrazolopyridinyl,imidazolonopyridinyl, thiazolopyridinyl, thiazolonopyridinyl,oxazolopyridinyl, oxazolonopyridinyl, isoxazolopyridinyl,isothiazolopyridinyl, triazolopyridinyl, imidazopyrimidinyl,pyrazolopyrimidinyl, imidazolonopyrimidinyl, thiazolopyridiminyl,thiazolonopyrimidinyl, oxazolopyridiminyl, oxazolonopyrimidinyl,isoxazolopyrimidinyl, isothiazolopyrimidinyl, triazolopyrimidinyl,dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyrimidinyl,phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl,pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl,quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl,benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl,tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl,benzoazepinyl, benzodiazepinyl, benzoxapinyl, and benzoxazepinyl;G3 is a non-fused bicyclic heteroaryl taken from the group consisting ofpyridylpyridiminyl pyrimidinylpyrimidinyl, oxazolylpyrimidinyl,thiazolylpyrimidinyl, imidazolylpyrimidinyl, isoxazolylpyrimidinyl,isothiazolylpyrimidinyl, pyrazolylpyrimidinyl, triazolylpyrimidinyl,oxadiazoylpyrimidinyl, thiadiazoylpyrimidinyl, morpholinylpyrimidinyl,dioxothiomorpholinylpyrimidinyl, and thiomorpholinylpyrimidinyl;G4 is a heterocyclyl taken from the group consisting of oxetanyl,azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl,imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl,piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide,thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl,tropanyl, and homotropanyl;the A ring may be optionally substituted with one or more —X1-A1moieties;X1 is selected from the group consisting of—(CH₂)_(n)—(O)_(r)(CH₂)_(n)—, —(CH₂)_(n)—(NR3)_(r)-(CH₂)_(n),—(CH₂)_(n)—(S)_(r)—(CH₂)_(n)—, —(CH₂)_(n)—(C═O)_(r)—(CH₂)_(n),—(CH₂)_(n)—(C(═O)—NR3)_(r)-(CH₂)_(n)—, and—(CH₂)_(n)—(SO₂—NR3)_(r)-(CH₂)_(n)—, wherein any of the alkylenes may bestraight or branched chain;X2 is selected from the group consisting of C1-C6alkyl, branchedC2-C6alkyl, and a direct bond wherein E1 is directly linked to the NR3group of formula Ia;A1 is selected from the group consisting of hydrogen, aryl, G1, G2, G3,G4, C1-C6 alkyl, branched C3-C8alkyl, R19 substituted C3-C8-carbocyclyl,fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated,halogen, cyano, hydroxyl, —N(R4)₂, —R5, —C(O)N(R4)₂, C(O)R5,C1-C6alkoxy, and fluoroC1-C6alkoxy wherein the alkyl group is fully orpartially fluorinated;When A and A1 have one or more substitutable sp2-hybridized carbon atom,each respective sp2 hybridized carbon atom may be optionally substitutedwith a Z1 or Z3 substituent;when A and A1 have one or more substitutable sp3-hybridized carbon atom,each respective sp3 hybridized carbon atom may be optionally substitutedwith a Z2 or R3 substituent;when A and A1 have one or more substitutable nitrogen atom, eachrespective nitrogen atom may be optionally substituted with a Z4substituent;each Z1 is independently and individually selected from the groupconsisting of hydrogen, hydroxyC1-C6alkyl, C1-C6alkoxy,C1-C6alkoxyC1-C6alkyl, (R4)₂NC1-C6alkyl,(R4)₂NC2-C6alkylN(R4)-(CH₂)_(n), (R4)₂NC2-C6alkylO—(CH₂)_(n),(R3)₂N—C(═O)—, (R4)₂N—C(═O)—, (R4)₂N—CO—C1-C6alkyl-,C1-C6alkoxycarbonyl-, -carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl,(R3)₂NSO₂—, —SOR3, (R4)₂NSO₂—, —SO₂R3, —SOR4, —C(═O)R6, —C(═NOH)R6,—C(═NOR3)R6, —(CH₂)_(n)N(R4)C(O)R8, —(CH₂)_(n)-G1, —(CH₂)_(n)-G4,phenoxy, —(CH₂)_(n)O—(CH₂)_(n)-G1, —(CH₂)_(n)—O—(CH₂)_(n)-G4,—(CH₂)_(n)—NR3-(CH₂)_(n)-aryl, —(CH₂)_(n)—NR3-(CH₂)_(n)-G1,—(CH₂)_(n)—NR3-(CH₂)_(n)-G4, —S(O)₂R5, —N═S(O)R6R8, —S(O)(═NR3)R6,—(CH₂)_(n)NHC(O)NHS(O)₂R8, —(CH₂)_(n)NHS(O)₂NHC(O)R8, —C(O)NHS(O)₂R8,—S(O)₂NHC(O)R8, —(CH₂)_(n)NHC(O)(CH₂)_(n)R5,—(CH₂)_(n)NHS(O)₂(CH₂)_(n)R5, —(CH₂)_(n)C(O)NH(CH₂)_(q)R5,—(CH₂)_(n)C(O)R5, —(CH₂)_(n)OC(O)R5, —(CH₂)_(n)S(O)₂NH(CH₂)_(q)R5,—CH(OH)(CH₂)_(p)R5, —CH(OH)CH(OH)R4, —(CH₂)_(n)N(R4)₂, —(CH₂)_(n)R5,—C(═NH)R5, —C(═NH)N(R4)₂, —C(═NOR3)R5, —C(═NOR3)N(R4)₂, and —NHC(═NH)R8;in the event that Z1 contains an alkyl or alkylene moiety, such moietiesmay be further substituted with one or more C1-C6alkyls;each Z2 is independently and individually selected from the groupconsisting of hydrogen, aryl, C1-C6alkyl, C3-C8-carbocyclyl, hydroxyl,hydroxyC1-C6alkyl-, cyano, (R3)₂N—, (R4)₂N—, (R4)₂NC1-C6alkyl-,(R4)₂NC2-C6alkylN(R4)-(CH₂)_(n)—, (R4)₂NC2-C6 alkylO—(CH₂)_(n)—,(R3)₂N—C(═O)—, (R4)₂N—C(═O)—, (R4)₂N—CO—C1-C6 alkyl-, carboxyl,carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl,(R3)₂NSO₂—, (R4)₂NSO₂—, —SO₂R5, —SO₂R8, —(CH₂)_(n)N(R4)C(O)R8, —C(O)R8,═O, ═NOH, ═N(OR6), —(CH₂)_(n)-G1, —(CH₂)_(n)-G4,—(CH₂)_(n)—O—(CH₂)_(n)-G1, —(CH₂)_(n)—O—(CH₂)_(n)-G4,—(CH₂)_(n)—NR3-(CH₂)_(n)-aryl, —(CH₂)_(n)—NR3-(CH₂)_(n)-G1,—(CH₂)_(n)—NR3-(CH₂)_(n)-G4, —(CH₂)_(n)NHC(O)NHS(O)₂R8,—(CH₂)_(n)NHS(O)₂NHC(O)R8, —C(O)NHS(O)₂R8, —(CH₂)NHC(O)(CH₂)_(n)R5,—(CH₂)_(n)NHS(O)₂R5, —(CH₂)_(n)C(O)NH(CH₂)_(q)R5, —(CH₂)_(n)C(O)R5,—(CH₂)_(n)OC(O)R5, and —(CH₂)_(n)R5;in the event that Z2 contains an alkyl or alkylene moiety, such moietiesmay be further substituted with one or more C1-C6alkyls;each Z3 is independently and individually selected from the groupconsisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C8-carbocyclyl,halogen, fluoroalkyl wherein the alkyl moiety can be partially or fullyfluorinated, cyano, hydroxyl, methoxy, oxo, (R3)₂N—C(═O)—,(R4)₂N—C(═O)—, —N(R4)-C(═O)R8, (R3)₂NSO₂—, (R4)₂NSO₂—, —N(R4)SO₂R5,—N(R4)SO₂R8, —(CH₂)_(n)—N(R3)₂, —(CH₂)_(n)—N(R4)₂, —O—(CH₂)_(q)—N(R4)₂,—O—(CH₂)_(q)—O-alkyl, —N(R3)-(CH₂)_(q)—O-alkyl, —N(R3)-(CH₂)_(q)—N(R4)₂,—O—(CH₂)_(q)—R5, —N(R3)-(CH₂)_(q)—R5, —C(═O)R5, —C(═O)R8, and nitro;in the event that Z3 contains an alkyl or alkylene moiety, such moietiesmay be further substituted with one or more C1-C6alkyls;each Z4 is independently and individually selected from the groupconsisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl,(R4)₂N—C2-C6alkyl, (R4)₂N—C2-C6alkylN(R4)-C2-C6 alkyl,(R4)₂N—C2-C6alkyl-O—C2-C6alkyl, (R4)₂N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl, —C2-C6alkylN(R4)C(O)R8,R8-C(═NR3)-, —SO₂R8, —COR8, —(CH₂)_(n)G1, —(CH₂)_(n)G4,—(CH₂)_(q)—O—(CH₂)_(n)-G1, —(CH₂)_(q)—O—(CH₂)_(n)-G4,—(CH₂)_(q)—NR3-(CH₂)_(n)-G1, —(CH₂)_(q)—NR3-(CH₂)_(n)-G4,—(CH₂)_(q)NHC(O)(CH₂)_(n)R5, —(CH₂)_(q)C(O)NH(CH₂)_(q)R5,—(CH₂)_(q)C(O)R5, —(CH₂)_(q)OC(O)R5, —(CH₂)_(q)R5,—(CH₂)_(q)NR4(CH₂)_(q)R5, and —(CH₂)_(q)O(CH₂)_(q)R5;in the event that Z4 contains an alkyl or alkylene moiety, such moietiesmay be further substituted with one or more C1-C6alkyls;each Z6 is independently and individually selected from the groupconsisting of H, C1-C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy,—OR4, C1-C6alkylthio, (R3)₂N—, (R4)₂N—, —R5, —N(R3)COR8, —N(R4)COR8,—N(R3)SO₂R6-, —CON(R3)₂, —CON(R4)₂, —COR5, —SO₂N(R4)₂, halogen,fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated,cyano, fluoroC1-C6alkoxy wherein the alkyl is fully or partiallyfluorinated, —O—(CH₂)_(q)—N(R4)₂, —N(R3)-(CH₂)_(q)—N(R4)₂,—O—(CH₂)_(q)—O-alkyl, —N(R3)-(CH₂)_(q)—O-alkyl, —O—(CH₂)_(q)—R5,—N(R3)-(CH₂)_(q)—R5, —(NR3)_(r)—(CH₂)_(n)—R17, —(O)_(r)—R17,—(S)_(r)—R17, and —(CH₂)_(r)—R17;in the event that Z6 contains an alkyl or alkylene moiety, such moietiesmay be further substituted with one or more C1-C6alkyls;wherein each R3 is independently and individually selected from thegroup consisting of H, C1-C6alkyl, branched C3-C7alkyl,C3-C8carbocyclyl, and Z3-substituted phenyl;each R4 is independently and individually selected from the groupconsisting of H, C1-C6alkyl, hydroxyC1-C6alkyl, dihydroxyC1-C6alkyl,C1-C6 alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6alkyl,branched C1-C6halkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl,—(CH₂)_(p)—N(R7)₂, —(CH₂)—R5, —(CH₂)_(p)—C(O)N(R7)₂, —(CH₂)_(n)C(O)R5,—(CH₂)_(n)—C(O)OR3, C3-C8carbocyclyl, hydroxyl substitutedC3-C8carbocyclyl, alkoxy substituted C3-C8carbocyclyl, dihydroxysubstituted C3-C8carbocyclyl, and —(CH₂)_(n)—R17;each R5 is independently and individually selected from the groupconsisting of

and wherein the symbol (##) is the point of attachment of the R5 moiety;each R6 is independently and individually selected from the groupconsisting of C1-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, phenyl,G1, and G4;each R7 is independently and individually selected from the groupconsisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, dihydroxyC2-C6alkyl,C1-C6alkoxyC2-C6alkyl, branched C3-C7alkyl, branched hydroxyC2-C6 alkyl,branched C1-C6alkoxyC2-C6alkyl, branched dihydroxyC2-C6alkyl,—(CH₂)_(q)—R5, —(CH₂)_(n)—C(O)R5, —(CH₂)_(n)—C(O)OR3, C3-C8carbocyclyl,hydroxyl substituted C3-C8carbocyclyl, alkoxy substitutedC3-C8carbocyclyl, dihydroxy substituted C3-C8carbocyclyl, and—(CH₂)_(n)—R17;each R8 is independently and individually selected from the groupconsisting of C1-C6alkyl, branched C3-C7alkyl, fluoroalkyl wherein thealkyl moiety is partially or fully fluorinated, C3-C8carbocyclyl,Z3-substituted phenyl, Z3-substituted phenyl C1-C6alkyl, Z3-substitutedG1, Z3-substituted G1-C1-C6alkyl, Z2-substituted G4, Z2-substitutedG4-C1-C6alkyl, OH, C1-C6alkoxy, N(R3)₂, N(R4)₂, and R5;each R10 is independently and individually selected from the groupconsisting of CO₂H, CO₂C1-C6alkyl, CO—N(R4)₂, OH, C1-C6alkoxy, and—N(R4)₂;R16 is independently and individually selected from the group consistingof hydrogen, C1-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, halogen,fluoroalkyl wherein the alkyl moiety can be partially or fullyfluorinated, cyano, hydroxyl, C1-C6alkoxy, C1-C6-fluoroalkoxy whereinthe alkyl moiety can be partially or fully fluorinated, —N(R3)₂,—N(R4)₂, C2-C3alkynyl, and nitro;each R17 is taken from the group comprising phenyl, naphthyl, pyrrolyl,furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl,pyrazinyl, pyridazinyl, triazinyl, oxetanyl, azetadinyl,tetrahydrofuranyl, oxazolinyl, oxazolidinyl, pyranyl, thiopyranyl,tetrahydropyranyl, dioxalinyl, azepinyl, oxepinyl, diazepinyl,pyrrolidinyl, and piperidinyl;wherein R17 can be further substituted with one or more Z2, Z3 or Z4moieties;R19 is H or C1-C6 alkyl;wherein two R3 or R4 moieties are independently and individually takenfrom the group consisting of C1-C6alkyl and branched C3-C6alkyl,hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogenatom, said moieties may cyclize to form a C3-C7 heterocyclyl ring;and k is 1 or 2; n is 0-6; p is 1-4; q is 2-6; r is 0 or 1; t is 1-3.1.1 Compounds of Formula Ia which Exemplify Preferred E1-X2 Moieties

In an embodiment of section 1, preferred compounds have the structuresof formula Ib

1.2 Compounds of Formula Ia which Exemplify Preferred A Moieties

In an embodiment of section 1.1, preferred compounds have the structuresof formula Ic

1.3 Compounds of Formula Ia which Exemplify Preferred A1 Moieties

In an embodiment of section 1.2, preferred compounds have the structuresof formula Id

wherein A1 is selected from the group consisting of branched C3-C8alkyl,R19 substituted C3-C8carbocyclyl, C1-C6alkyl, fluoroC1-C6alkyl whereinthe alkyl is fully or partially fluorinated, Z3-substituted phenyl, andZ3-substituted G1;and wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.1.3a Compounds of Formula Id which Exemplify More Preferred X2-E1Moieties

In an embodiment of section 1.3, preferred compounds have the structuresof formula Ie

1.3b Additional Compounds of Formula Id which Exemplify More PreferredX2-E1 Moieties

In another embodiment of section 1.3, preferred compounds have thestructures of formula If

wherein R16 is methyl, cyano, —CCH, fluorine or chlorine.1.4 Compounds of Formula Ia which Exemplify Additional Preferred A1Moieties

In a different embodiment of section 1.2, additional preferred compoundshave the structures of formula Ig

wherein A1 is selected from the group consisting of branched C3-C8alkyl,R19 substituted C3-C8carbocyclyl, C1-C6alkyl, fluoroC1-C6alkyl whereinthe alkyl is fully or partially fluorinated, Z3-substituted phenyl, andZ3-substituted G1;and wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.1.4a Additional Compounds of Formula Ig which Exemplify More PreferredX2-E1 Moieties

In an embodiment of section 1.4, preferred compounds have the structuresof formula Ih

1.4b Additional Compounds of Formula Ig which Exemplify, More PreferredX2-E1 Moieties

In another embodiment of section 1.4, preferred compounds have thestructures of formula Ii

wherein R16 is C1-C6alkyl, cyano, —CCH, fluorine or chlorine.1.5 Compounds of Formula Ia which Exemplify Additionally Preferred AMoieties

In a different embodiment of section 1.1, additional preferred compoundshave the structures of formula Ij

wherein A1 is selected from the group consisting of branchedZ2-substituted C3-C8alkyl, R19 substituted C3-C8carbocyclyl,Z2-substituted C1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fullyor partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;and wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.1.5a Additional Compounds of Formula Ij which Exemplify More PreferredX2-E1 Moieties

In an embodiment of section 1.5, preferred compounds have the structuresof formula Ik

1.5b Additional Compounds of Formula Ij which Exemplify More PreferredX2-E1 Moieties

In another embodiment of section 1.5, preferred compounds have thestructures of formula Il

and wherein R16 is methyl, cyano, —CCH, fluorine or chlorine.1.6 Compounds of Formula Ia which Exemplify Additionally Preferred AMoieties

In a different embodiment of section 1.1, additional preferred compoundshave the structures of formula Im

wherein A1 is selected from the group consisting of hydrogen,Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl,Z2-substituted C1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fullyor partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;and wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.1.6a Additional Compounds of Formula Im which Exemplify More PreferredX2-E1 Moieties

In an embodiment of section 1.6, preferred compounds have the structuresof formula In

1.6b Additional Compounds of Formula Im which Exemplify More PreferredX2-E1 Moieties

In another embodiment of section 1.6, preferred compounds have thestructures of formula Io

wherein R16 is C1-C6alkyl, cyano, —CCH, fluorine or chlorine.1.7 Compounds of Formula Ia which Exemplify Additionally Preferred AMoieties

In a different embodiment of section 1.1, additional preferred compoundshave the structures of formula Ip

wherein A1 is selected from the group consisting of Z2-substitutedbranched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substitutedC1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partiallyfluorinated, Z3-substituted phenyl, and Z3-substituted G1;and wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.1.7a Additional Compounds of Formula Ip which Exemplify More PreferredX2-E1 Moieties

In an embodiment of section 1.7, preferred compounds have the structuresof formula Iq

1.7b Additional Compounds of Formula Ip which Exemplify More PreferredX2-E1 Moieties

In another embodiment of section 1.7, preferred compounds have thestructures of formula Ir

and wherein R16 is methyl, cyano, —CCH, fluorine or chlorine.1.8 Compounds of Formula Ia which Exemplify Additionally Preferred AMoieties

In a different embodiment of section 1.1, additional preferred compoundshave the structures of formula Is

wherein the hashed bond is a saturated or unsaturated bond;and wherein A1 is selected from the group consisting of hydrogen,Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl,Z2-substituted C1-C6alkyl, halogen, fluoroC1-C6alkyl, cyano,C1-C6alkoxy, fluoroC1-C6alkoxy, fluoroC1-C6alkyl wherein the alkyl isfully or partially fluorinated, Z3-substituted phenyl, andZ3-substituted G1;and wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.1.8a Additional Compounds of Formula Is which Exemplify More PreferredX2-E1 Moieties

In an embodiment of section 1.8, preferred compounds have the structuresof formula It

1.8b Additional Compounds of Formula Is which Exemplify More PreferredX2-E1 Moieties

In another embodiment of section 1.8, preferred compounds have thestructures of formula Iu

wherein R16 is methyl, cyano, —CCH, fluorine or chlorine.1.9 Compounds of Formula Ia which Exemplify Additionally Preferred aMoieties

In a different embodiment of section 1.1, additional preferred compoundshave the structures of formula Iv

wherein the hashed bond is a saturated or unsaturated bond;and wherein A1 is selected from the group consisting of hydrogen,Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl,Z2-substituted C1-C6alkyl, halogen, fluoroC1-C6alkyl, cyano,C1-C6alkoxy, fluoroC1-C6alkoxy, fluoroC1-C6alkyl wherein the alkyl isfully or partially fluorinated, Z3-substituted phenyl, andZ3-substituted G1;and wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.1.9a Additional Compounds of Formula Iv which Exemplify More PreferredX2-E1 Moieties

In an embodiment of section 1.9, preferred compounds have the structuresof formula Iw

1.9b Additional Compounds of Formula Iv which Exemplify More PreferredX2-E1 Moieties

In another embodiment of section 1.9, preferred compounds have thestructures of formula Ix

wherein R16 is C1-C6alkyl, cyano, —CCH, fluorine or chlorine.1.10 Compounds of Formula Ia which Exemplify Additionally Preferred AMoieties

In a different embodiment of section 1.1, additional preferred compoundshave the structures of formula Iy

wherein A1 is selected from the group consisting of Z2-substitutedbranched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substitutedC1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partiallyfluorinated, Z3-substituted phenyl, and Z3-substituted G1;and wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.1.10a Additional Compounds of Formula Iy which Exemplify More PreferredX2-E1 Moieties

In an embodiment of section 1.10, preferred compounds have thestructures of formula Iz

1.10b Additional Compounds of Formula Iy which Exemplify More PreferredX2-E1 Moieties

In another embodiment of section 1.10, preferred compounds have thestructures of formula Iaa

wherein R16 is C1-C6alkyl, cyano, —CCH, fluorine or chlorine.1.11 Compounds of Formula Ia which Exemplify Additionally Preferred AMoieties

In a different embodiment of section 1.1, additional preferred compoundshave the structures of formula Ibb

wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.1.11a Additional Compounds of Formula Ibb which Exemplify More PreferredX2-E1 Moieties

In an embodiment of section 1.11, preferred compounds have thestructures of formula Icc

1.11 b Additional Compounds of Formula Ibb which Exemplify MorePreferred X2-E1 Moieties

In another embodiment of section 1.11, preferred compounds have thestructures of formula Idd

wherein R16 is C1-C6alkyl, cyano, —CCH, fluorine or chlorine.1.12 Compounds of Formula Ia which Exemplify Additionally Preferred AMoieties

In a different embodiment of section 1.1, additional preferred compoundshave the structures of formula Iee

wherein Q1 and Q2 individually and independently taken from the groupconsisting of N and CH;and wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.1.12a Additional Compounds of Formula Iee which Exemplify More PreferredX2-E1 Moieties

In an embodiment of section 1.12 preferred compounds have the structuresof formula Iff

1.12b Additional Compounds of Formula Iee which Exemplify More PreferredX2-E1 Moieties

In another embodiment of section 1.12, preferred compounds have thestructures of formula Igg

wherein R16 is C1-C6alkyl, cyano, —CCH, fluorine or chlorine.1.13 Compounds of Formula Ia which Exemplify Additionally Preferred aMoieties

In a different embodiment of section 1.1, additional preferred compoundshave the structures of formula Ihh

and wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.1.13a Additional Compounds of Formula Ihh which Exemplify More PreferredX2-E1 Moieties

In an embodiment of section 1.13, preferred compounds have thestructures of formula Iii

1.13b Additional Compounds of Formula Ihh which Exemplify More PreferredX2-E1 Moieties

In another embodiment of section 1.13, preferred compounds have thestructures of formula Ijj

and wherein R16 is methyl, cyano, —CCH, fluorine or chlorine.1.14 Compounds of Formula Ia which Exemplify, Additionally Preferred AMoieties

In a different embodiment of section 1.1, additional preferred compoundshave the structures of formula Ikk

wherein Q6 is N or C-A1;wherein A1 is selected from the group consisting of hydrogen,Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl,Z2-substituted C1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fullyor partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;and wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.1.14a Additional Compounds of Formula Ikk which Exemplify More PreferredX2-E1 Moieties

In an embodiment of section 1.14, preferred compounds have thestructures of formula III

1.14b Additional Compounds of Formula Lick which Exemplify MorePreferred X2-E1 Moieties

In another embodiment of section 1.14, preferred compounds have thestructures of formula Imm

wherein R16 is C1-C6alkyl, cyano, —CCH, fluorine or chlorine.1.15 Compounds of Formula Ia which Exemplify Additionally Preferred aMoieties

In a different embodiment of section 1.1, additional preferred compoundshave the structures of formula Inn

wherein A1 is selected from the group consisting of hydrogen,Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl,Z2-substituted C1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fullyor partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;and wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.1.15a Additional Compounds of Formula Inn which Exemplify More PreferredX2-E1 Moieties

In an embodiment of section 1.15, preferred compounds have thestructures of formula Ioo

1.15b Additional Compounds of Formula Inn which Exemplify More PreferredX2-E1 Moieties

In another embodiment of section 1.15, preferred compounds have thestructures of formula Ipp

wherein R16 is C1-C6alkyl, cyano, —CCH, fluorine or chlorine.1.16 Compounds of Formula Ia which Exemplify Additionally Preferred AMoieties

In a different embodiment of section 1.1, additional preferred compoundshave the structures of formula Iqq

wherein Q3, Q4 and Q5 are selected from the group consisting of N-A1 andC-A1, and only one of Q3, Q4, or Q5 is N-A1;and wherein A1 is selected from the group consisting of hydrogen,Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl,Z2-substituted C1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fullyor partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;and wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.1.16a Additional Compounds of Formula Iqq which Exemplify More PreferredX2-E1 Moieties

In an embodiment of section 1.16, preferred compounds have thestructures of formula Irr

1.16b Additional Compounds of Formula Iqq which Exemplify More PreferredX2-E1 Moieties

In another embodiment of section 1.16, preferred compounds have thestructures of formula Iss

wherein R16 is C1-C6alkyl, cyano, —CCH, fluorine or chlorine.

1.17 Methods 1.17a Methods of Protein Modulation

The invention includes methods of modulating kinase activity of RAFkinases and other kinases in the RAS-RAF-MEK-ERK-MAP kinase pathwayincluding, but not limited to, A-Raf, B-Raf, and C-Raf. The kinases maybe wildtype kinases, oncogenic forms thereof, aberrant fusion proteinsthereof or polymorphs of any of the foregoing. The method comprises thestep of contacting the kinase species with compounds of the inventionand especially those set forth in sections 1.1-1.16. The kinase speciesmay be activated or unactivated, and the species may be modulated byphosphorylations, sulfation, fatty acid acylations glycosylations,nitrosylation, cystinylation (i.e. proximal cysteine residues in thekinase react with each other to form a disulfide bond) or oxidation. Thekinase activity may be selected from the group consisting of catalysisof phospho transfer reactions, kinase cellular localization, andrecruitment of other proteins into signaling complexes throughmodulation of kinase conformation.

1.17b Treatment Methods

The methods of the invention, especially those of sections 1.1-1.16,also include treating individuals suffering from a condition selectedfrom the group consisting of chronic myelogenous leukemia, acutelymphocytic leukemia, gastrointestinal stromal tumors,hypereosinophillic syndrome, glioblastomas, ovarian cancer, pancreaticcancer, prostate cancer, lung cancers, breast cancers, kidney cancers,cervical carcinomas, metastasis of primary solid tumor secondary sites,ocular diseases characterized by hyperproliferation leading to blindnessincluding various retinopathies including diabetic retinopathy andage-related macular degeneration, rheumatoid arthritis, melanomas, coloncancer, thyroid cancer, a disease caused by a mutation in theRAS-RAF-MEK-ERK-MAP kinase pathway, human inflammation, rheumatoidspondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septicshock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome,adult respiratory distress syndrome, stroke, reperfusion injury, neuraltrauma, neural ischemia, psoriasis, restenosis, chronic obstructivepulmonary disease, bone resorptive diseases, graft-versus-host reaction,Chron's disease, ulcerative colitis, inflammatory bowel disease,pyresis, and combinations thereof,

1.18 Pharmaceutical Preparations

The compounds of the invention, especially those of sections 1.1-1.16,may form a part of a pharmaceutical composition by combining one or moresuch compounds with a pharmaceutically acceptable carrier. Additionally,the compositions may include an additive selected from the groupconsisting of adjuvants, excipients, diluents, and stabilizers.

2. Second Aspect of the Invention—Compounds, Methods, Preparations andAdducts

In the first aspect of the invention, compounds are of the formula IIa

wherein X—Y in order is C═N or N—CH2;wherein one of Q1 and Q2 is N and the other is CR3;wherein E1 is selected from the group consisting cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl,thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl,pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl,pyrimidinyl and naphthyl;wherein A is selected from the group consisting of phenyl, naphthyl,C3-C8carbocyclyl, indanyl, tetralinyl, indenyl, G1, G2, G3, G4 and—CHR4R8;G1 is a heteroaryl taken from the group consisting of pyrrolyl, furyl,thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl,pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl,pyridazinyl, triazinyl, pyridinyl, and pyrimidinyl;G2 is a fused bicyclic heteroaryl taken from the group consisting ofindolyl, indolinyl, isoindolyl, isoindolinyl, indazolyl, benzofuranyl,benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl,benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl,benzimidazolonyl, benztriazolyl, imidazopyridinyl, pyrazolopyridinyl,imidazolonopyridinyl, thiazolopyridinyl, thiazolonopyridinyl,oxazolopyridinyl, oxazolonopyridinyl, isoxazolopyridinyl,isothiazolopyridinyl, triazolopyridinyl, imidazopyrimidinyl,pyrazolopyrimidinyl, imidazolonopyrimidinyl, thiazolopyridiminyl,thiazolonopyrimidinyl, oxazolopyridiminyl, oxazolonopyrimidinyl,isoxazolopyrimidinyl, isothiazolopyrimidinyl, triazolopyrimidinyl,dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyrimidinyl,phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl,pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl,quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl,benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl,tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl,benzoazepinyl, benzodiazepinyl, benzoxapinyl, and benzoxazepinyl;G3 is a non-fused bicyclic heteroaryl taken from the group consisting ofpyridylpyridiminyl pyrimidinylpyrimidinyl, oxazolylpyrimidinyl,thiazolylpyrimidinyl, imidazolylpyrimidinyl, isoxazolylpyrimidinyl,isothiazolylpyrimidinyl, pyrazolylpyrimidinyl, triazolylpyrimidinyl,oxadiazoylpyrimidinyl, thiadiazoylpyrimidinyl, morpholinylpyrimidinyl,dioxothiomorpholinylpyrimidinyl, and thiomorpholinylpyrimidinyl;G4 is a heterocyclyl taken from the group consisting of oxetanyl,azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl,imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl,piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide,thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl,tropanyl, and homotropanyl;the A ring may be optionally substituted with one or more —X1-A1moieties;X1 is selected from the group consisting of—(CH₂)_(n)—(O)_(r)—(CH₂)_(n)—, —(CH₂)_(n)—(NR3)_(r)-(CH₂)_(n)—,—(CH₂)_(n)—(S)_(r)—(CH₂)_(n)—, —(CH₂)_(n)—(C═O)_(r)—(CH₂)_(n)—,—(CH₂)_(n)—(C(═O)—NR3)_(r)-(CH₂)_(n)—, and—(CH₂)_(n)—(SO₂—NR3)_(r)-(CH₂)_(n)—, wherein any of the alkylenes may bestraight or branched chain;X2 is selected from the group consisting of C1-C6alkyl, branchedC2-C6alkyl, and a direct bond wherein E1 is directly linked to the NR3group of formula Ia;A1 is selected from the group consisting of hydrogen, aryl, G1, G2, G3,G4, C1-C6 alkyl, branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl,fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated,halogen, cyano, hydroxyl, —N(R4)₂, —R5, —C(O)N(R4)₂, C(O)R5,C1-C6alkoxy, and fluoroC1-C6alkoxy wherein the alkyl group is fully orpartially fluorinated;

When A and A1 have one or more substitutable sp2-hybridized carbon atom,each respective sp2 hybridized carbon atom may be optionally substitutedwith a Z1 or Z3 substituent;

when A and A1 have one or more substitutable sp3-hybridized carbon atom,each respective sp3 hybridized carbon atom may be optionally substitutedwith a Z2 or R3 substituent;when A and A1 have one or more substitutable nitrogen atom, eachrespective nitrogen atom may be optionally substituted with a Z4substituent;each Z1 is independently and individually selected from the groupconsisting of hydrogen, hydroxyC1-C6alkyl, C1-C6alkoxy,C1-C6alkoxyC1-C6alkyl, (R4)₂NC1-C6alkyl,(R4)₂NC2-C6alkylN(R4)-(CH₂)_(n), (R4)₂NC2-C6alkylO—(CH₂)_(n),(R3)₂N—C(═O)—, (R4)₂N—C(═O)—, (R4)₂N—CO—C1-C6alkyl-, C1-C6alkoxycarbonyl-, -carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl,(R3)₂NSO₂—, —SOR3, (R4)₂NSO₂—, —SO₂R3, —SOR4, —C(═O)R6, —C(═NOH)R6,—C(═NOR3)R6, —(CH₂)_(n)N(R4)C(O)R8, —(CH₂)_(n)-G1, —(CH₂)_(n)-G4,phenoxy, —(CH₂)_(n)—O—(CH₂)_(n)-G1, —(CH₂)_(n)—O—(CH₂)_(n)-G4,—(CH₂)_(n)—NR3-(CH₂)_(n)-aryl, —(CH₂)_(n)—NR3-(CH₂)_(n)-G1,—(CH₂)_(n)—NR3-(CH₂)_(n)-G4, —S(O)₂R5, —N═S(O)R6R8, —S(O)(═NR3)R6,—(CH₂)_(n)NHC(O)NHS(O)₂R8, —(CH₂)_(n)NHS(O)₂NHC(O)R8, —C(O)NHS(O)₂R8,—S(O)₂NHC(O)R8, —(CH₂)_(n)NHC(O)(CH₂)_(n)R5,—(CH₂)_(n)NHS(O)₂(CH₂)_(n)R5, —(CH₂)_(n)C(O)NH(CH₂)_(n)R5,—(CH₂)_(n)C(O)R5, —(CH₂)_(n)OC(O)R5, —(CH₂)_(n)S(O)₂NH(CH₂)_(q)R5,—CH(OH)(CH₂)_(p)R5, —CH(OH)CH(OH)R4, —(CH₂)_(n)N(R4)₂, —(CH₂)_(n)R5,—C(═NH)R5, —C(═NH)N(R4)₂, —C(═NOR3)R5, —C(═NOR3)N(R4)₂, and —NHC(═NH)R8;in the event that Z1 contains an alkyl or alkylene moiety, such moietiesmay be further substituted with one or more C1-C6alkyls;each Z2 is independently and individually selected from the groupconsisting of hydrogen, aryl, C1-C6alkyl, C3-C8carbocyclyl, hydroxyl,hydroxyC1-C6alkyl-, cyano, (R3)₂N—, (R4)₂N—, (R4)₂NC1-C6alkyl-,(R4)₂NC2-C6alkylN(R4)-(CH₂)_(n)—, (R4)₂NC2-C6alkylO—(CH₂)_(n)—,(R3)₂N—C(═O)—, (R4)₂N—C(═O)—, (R4)₂N—CO—C1-C6alkyl-, carboxyl,carboxyC1-C6alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl,(R3)₂NSO₂—, (R4)₂NSO₂—, —SO₂R5, —SO₂R8, —(CH₂)_(n)N(R4)C(O)R8, —C(O)R8,═O, ═NOH, ═N(OR6), —(CH₂)_(n)-G1, —(CH₂)_(n)-G4, —(CH₂)_(n)—O—(CH₂)-G1,—(CH₂)_(n)—O— (CH₂)_(n)-G4, —(CH₂)_(n)—NR3-(CH₂)_(n)-aryl,—(CH₂)_(n)—NR3-(CH₂)_(n)-G1, —(CH₂)_(n)—NR3-(CH₂)_(n)-G4,—(CH₂)_(n)NHC(O)NHS(O)₂R8, —(CH₂)_(n)NHS(O)₂NHC(O)R8, —C(O)NHS(O) ₂R8,—(CH₂)NHC(O)(CH₂)_(n)R5, —(CH₂)_(n)NHS(O)₂R5,—(CH₂)_(n)C(O)NH(CH₂)_(q)R5, —(CH₂)_(n)C(O)R5, —(CH₂)_(n)OC(O)R5, and—(CH₂)_(n)R5;in the event that Z2 contains an alkyl or alkylene moiety, such moietiesmay be further substituted with one or more C1-C6alkyls;each Z3 is independently and individually selected from the groupconsisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl,halogen, fluoroalkyl wherein the alkyl moiety can be partially or fullyfluorinated, cyano, hydroxyl, methoxy, oxo, (R3)₂N—C(═O)—,(R4)₂N—C(═O)—, —N(R4)-C(═O)R8, (R3)₂NSO₂—, (R4)₂NSO₂—, —N(R4)SO₂R5,—N(R4)SO₂R5, —(CH₂)_(n)—N(R3)₂, —(CH₂)_(n)—N(R4)₂, —O—(CH₂)_(q)—N(R4)₂,—O—(CH₂)_(q)—O-alkyl, —N(R3)-(CH₂)_(q)—O-alkyl, —N(R3)-(CH₂)_(q)—N(R4)₂,—O—(CH₂)_(q)—R5, —N(R3)-(CH₂)_(q)—R5, —C(═O)R5, —C(═O)R8, and nitro;in the event that Z3 contains an alkyl or alkylene moiety, such moietiesmay be further substituted with one or more C1-C6alkyls;each Z4 is independently and individually selected from the groupconsisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, C1-C6 alkoxyC2-C6alkyl,(R4)₂N—C2-C6alkyl, (R4)₂N—C2-C6alkylN(R4)-C2-C6alkyl,(R4)₂N—C2-C6alkyl-O—C2-C6alkyl, (R4)₂N—CO—C1-C6alkyl, carboxyC1-C6alkyl,C1-C6alkoxycarbonylC1-C6alkyl, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-,—SO₂R8, —COR8, (CH₂)_(n)-G1, —(CH₂)_(n)-G4, —(CH₂)_(q)—O—(CH₂)_(n)-G1,—(CH₂)_(q)—O—(CH₂)_(n)-G4, —(CH₂)_(q)—NR3-(CH₂)-G1,—(CH₂)_(q)—NR3-(CH₂)_(n)-G4, —(CH₂)_(q)NHC(O)(CH₂)_(n)R5,—(CH₂)₄C(O)NH(CH₂)_(n)R5, —(CH₂)_(q)C(O)R5, —(CH₂)_(q)OC(O)R5,—(CH₂)_(q)R5, —(CH₂)_(q)NR4(CH₂)_(q)R5, and —(CH₂)_(q)O(CH₂)_(q)R5;in the event that Z4 contains an alkyl or alkylene moiety, such moietiesmay be further substituted with one or more C1-C6alkyls;each Z6 is independently and individually selected from the groupconsisting of H, C1-C6alkyl, branched C3-C7alkyl, hydroxyl, C1-C6alkoxy,—OR4, C1-C6alkylthio, (R3)₂N—, (R4)₂N—, —R5, —N(R3)COR8, —N(R4)COR8,—N(R3)SO₂R6-, —CON(R3)₂, —CON(R4)₂, —COR5, —SO₂N(R4)₂, halogen,fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated,cyano, fluoroC1-C6alkoxy wherein the alkyl is fully or partiallyfluorinated, —O—(CH₂)_(q)—N(R4)₂, —N(R3)-(CH₂)_(q)—N(R4)₂,—O—(CH₂)_(q)—O-alkyl, —N(R3)-(CH₂)_(q)—O-alkyl, —O—(CH₂)_(q)—R5,—N(R3)-(CH₂)_(q)—R5, —(NR3)_(r)—(CH₂)_(n)—R17, —(O)_(r)—R17,—(S)_(r)—R17, and —(CH₂)_(r)—R17;in the event that Z6 contains an alkyl or alkylene moiety, such moietiesmay be further substituted with one or more C1-C6alkyls;

wherein each R3 is independently and individually selected from thegroup consisting of H, C1-C6alkyl, branched C3-C7alkyl,C3-C8carbocyclyl, and Z3-substituted phenyl;

each R4 is independently and individually selected from the groupconsisting of H, C1-C6alkyl, hydroxyC1-C6alkyl, dihydroxyC1-C6alkyl,C1-C6alkoxyC1-C6alkyl, branched C3-C7alkyl, branched hydroxyC1-C6alkyl,branched C1-C6alkoxyC1-C6alkyl, branched dihydroxyC1-C6alkyl,—(CH₂)_(p)—N(R7)₂, —(CH₂)_(p)—R5, —(CH₂)_(p)—C(O)N(R7)₂,—(CH₂)_(n)C(O)R5, —(CH₂)_(n)—C(O)OR3, C3-C8carbocyclyl, hydroxylsubstituted C3-C8carbocyclyl, alkoxy substituted C3-C8carbocyclyl,dihydroxy substituted C3-C8carbocyclyl, and —(CH₂)_(n)—R17;each R5 is independently and individually selected from the groupconsisting of

and wherein the symbol (##) is the point of attachment of the R5 moiety;each R6 is independently and individually selected from the groupconsisting of C1-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, phenyl,G1, and G4;each R7 is independently and individually selected from the groupconsisting of H, C1-C6alkyl, hydroxyC2-C6alkyl, dihydroxyC2-C6alkyl,C1-C6alkoxyC2-C6alkyl, branched C3-C7alkyl, branched hydroxyC2-C6 alkyl,branched C1-C6alkoxyC2-C6alkyl, branched dihydroxyC2-C6alkyl,—(CH₂)_(q)—R5, —(CH₂)_(n)—C(O)R5, —(CH₂)_(n)—C(O)OR3, C3-C8carbocyclyl,hydroxyl substituted C3-C8carbocyclyl, alkoxy substitutedC3-C8carbocyclyl, dihydroxy substituted C3-C8carbocyclyl, and—(CH₂)_(n)—R17;each R8 is independently and individually selected from the groupconsisting of C1-C6alkyl, branched C3-C7alkyl, fluoroalkyl wherein thealkyl moiety is partially or fully fluorinated, C3-C8carbocyclyl,Z3-substituted phenyl, Z3-substituted phenyl C1-C6alkyl, Z3-substitutedG1, Z3-substituted G1-C1-C6alkyl, Z2-substituted G4, Z2-substitutedG4-C1-C6alkyl, OH, C1-C6alkoxy, N(R3)₂, N(R4)₂, and R5;each R10 is independently and individually selected from the groupconsisting of CO₂H, CO₂C1-C6alkyl, CO—N(R4)₂, OH, C1-C6alkoxy, and—N(R4)₂;R16 is independently and individually selected from the group consistingof hydrogen, C1-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, halogen,fluoroalkyl wherein the alkyl moiety can be partially or fullyfluorinated, cyano, hydroxyl, C1-C6alkoxy, C1-C6fluoroalkoxy wherein thealkyl moiety can be partially or fully fluorinated, —N(R3)₂, —N(R4)₂,C2-C3alkynyl, and nitro;each R17 is taken from the group comprising phenyl, naphthyl, pyrrolyl,furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl,pyrazinyl, pyridazinyl, triazinyl, oxetanyl, azetadinyl,tetrahydrofuranyl, oxazolinyl, oxazolidinyl, pyranyl, thiopyranyl,tetrahydropyranyl, dioxalinyl, azepinyl, oxepinyl, diazepinyl,pyrrolidinyl, and piperidinyl;wherein R17 can be further substituted with one or more Z2, Z3 or Z4moieties;R19 is H or C1-C6 alkyl;wherein two R3 or R4 moieties are independently and individually takenfrom the group consisting of C1-C6alkyl and branched C3-C6alkyl,hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogenatom, said moieties may cyclize to form a C3-C7 heterocyclyl ring; and kis 1 or 2; n is 0-6; p is 1-4; q is 2-6; r is 0 or 1; t is 1-3.2.1 Compounds of Formula IIa which Exemplify; Preferred E1-X2 Moieties

In an embodiment of section 2, preferred compounds have the structuresof formula IIb

2.2 Compounds of Formula IIa which Exemplify Preferred A Moieties

In an embodiment of section 2.1, preferred compounds have the structuresof formula IIc

2.3 Compounds of Formula IIa which Exemplify Preferred A1 Moieties

In an embodiment of section 2.2, preferred compounds have the structuresof formula IId

wherein A1 is selected from the group consisting of branched C3-C8alkyl,R19 substituted C3-C8carbocyclyl, C1-C6alkyl, fluoroC1-C6alkyl whereinthe alkyl is fully or partially fluorinated, Z3-substituted phenyl, andZ3-substituted G1;and wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.2.3a Compounds of Formula IId which Exemplify More Preferred X2-E1Moieties

In an embodiment of section 2.3, preferred compounds have the structuresof formula IIe

2.3b Additional Compounds of Formula IId which Exemplify More PreferredX2-E1 Moieties

In another embodiment of section 2.3, preferred compounds have thestructures of Formula IIf

wherein R16 is methyl, cyano, —CCH, fluorine or chlorine.2.4 Compounds of Formula IIa which Exemplify Additional Preferred A1Moieties

In a different embodiment of section 2.2, additional preferred compoundshave the structures of formula IIg

wherein A1 is selected from the group consisting of branched C3-C8alkyl,R19 substituted C3-C8carbocyclyl, C1-C6alkyl, fluoroC1-C6alkyl whereinthe alkyl is fully or partially fluorinated, Z3-substituted phenyl, andZ3-substituted G1;

and wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.

2.4a Additional Compounds of Formula IIg which Exemplify More PreferredX2-E1 Moieties

In an embodiment of section 2.4, preferred compounds have the structuresof formula IIh

2.4b Additional Compounds of Formula IIg which Exemplify More PreferredX2-E1 Moieties

In another embodiment of section 2.4, preferred compounds have thestructures of formula IIi

wherein R16 is methyl, cyano, —CCH, fluorine or chlorine.2.5 Compounds of Formula IIa which Exemplify Additionally Preferred AMoieties

In a different embodiment of section 2.1, additional preferred compoundshave the structures of formula IIj

wherein A1 is selected from the group consisting of branchedZ2-substituted C3-C8alkyl, R19 substituted C3-C8carbocyclyl,Z2-substituted C1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fullyor partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;and wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.2.5a Additional Compounds of Formula IIj which Exemplify More PreferredX2-E1 Moieties

In an embodiment of section 2.5, preferred compounds have the structuresof formula IIk

2.5b Additional Compounds of Formula IIf which Exemplify More PreferredX2-E1 Moieties

In another embodiment of section 2.5, preferred compounds have thestructures of formula IIl

wherein R16 is methyl, cyano, —CCH, fluorine or chlorine.2.6 Compounds of Formula IIa which Exemplify Additionally Preferred AMoieties

In a different embodiment of section 2.1, additional preferred compoundshave the structures of formula IIm

wherein A1 is selected from the group consisting of hydrogen,Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl,Z2-substituted C1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fullyor partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;and wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.2.6a Additional Compounds of Formula IIm which Exemplify More PreferredX2-E1 Moieties

In an embodiment of section 2.6, preferred compounds have the structuresof formula IIn

2.6b Additional Compounds of Formula IIn which Exemplify More PreferredX2-E1 Moieties

In another embodiment of section 2.6, preferred compounds have thestructures of formula no

wherein R16 is C1-C6alkyl, cyano, —CCH, fluorine or chlorine.2.7 Compounds of Formula IIa which Exemplify additionally preferred AMoieties

In a different embodiment of section 2.1, additional preferred compoundshave the structures of formula IIp

wherein A1 is selected from the group consisting of Z2-substitutedbranched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substitutedC1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partiallyfluorinated, Z3-substituted phenyl, and Z3-substituted G1;and wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.2.7a Additional Compounds of Formula IIp which Exemplify More PreferredX2-E1 Moieties

In an embodiment of section 2.7, preferred compounds have the structuresof formula IIq

2.7b Additional Compounds of Formula IIp which Exemplify More PreferredX2-E1 Moieties

In another embodiment of section 2.7, preferred compounds have thestructures of formula IIr

and wherein R16 is methyl, cyano, —CCH, fluorine or chlorine.2.8 Compounds of Formula IIa which Exemplify Additionally Preferred aMoieties

In a different embodiment of section 2.1, additional preferred compoundshave the structures of formula IIs

wherein the hashed bond is a saturated or unsaturated bond;and wherein A1 is selected from the group consisting of hydrogen,Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl,Z2-substituted C1-C6alkyl, halogen, fluoroC1-C6alkyl, cyano,C1-C6alkoxy, fluoroC1-C6alkoxy, fluoroC1-C6alkyl wherein the alkyl isfully or partially fluorinated, Z3-substituted phenyl, andZ3-substituted G1;and wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.2.8a Additional Compounds of Formula IIs which Exemplify More PreferredX2-E1 Moieties

In an embodiment of section 2.8, preferred compounds have the structuresof formula IIt

2.8b Additional Compounds of Formula IIs which Exemplify More PreferredX2-E1 Moieties In another embodiment of section 2.8, preferred compoundshave the structures of formula nu

and wherein R16 is C1-C6alkyl, cyano, —CCH, fluorine or chlorine.2.9 Compounds of Formula IIa which Exemplify Additionally Preferred AMoieties

In a different embodiment of section 2.1, additional preferred compoundshave the structures of formula IIv

wherein the hashed bond is a saturated or unsaturated bond;and wherein A1 is selected from the group consisting of hydrogen,Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl,Z2-substituted C1-C6alkyl, halogen, fluoroC1-C6alkyl, cyano,C1-C6alkoxy, fluoroC1-C6alkoxy, fluoroC1-C6alkyl wherein the alkyl isfully or partially fluorinated, Z3-substituted phenyl, andZ3-substituted G1;and wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.2.9a Additional Compounds of Formula IIv which Exemplify More PreferredX2-E1 Moieties

In an embodiment of section 2.9, preferred compounds have the structuresof formula IIw

2.9b Additional Compounds of Formula IIv which Exemplify More PreferredX2-E1 Moieties

In another embodiment of section 2.9, preferred compounds have thestructures of formula IIx

and wherein R16 is C1-C6alkyl, cyano, —CCH, fluorine or chlorine.2.10 Compounds of Formula IIa which Exemplify Additionally Preferred AMoieties

In a different embodiment of section 2.1, additional preferred compoundshave the structures of formula IIy

wherein A1 is selected from the group consisting of Z2-substitutedbranched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substitutedC1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fully or partiallyfluorinated, Z3-substituted phenyl, and Z3-substituted G1;and wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.2.10a Additional Compounds of Formula IIy which Exemplify More PreferredX2-E1 Moieties

In an embodiment of section 2.10, preferred compounds have thestructures of formula IIz

2.10b Additional Compounds of Formula IIy which Exemplify More PreferredX2-E1 Moieties

In another embodiment of section 2.10, preferred compounds have thestructures of formula IIaa

wherein R16 is methyl, cyano, —CCH, fluorine or chlorine.2.11 Compounds of Formula IIa which Exemplify Additionally Preferred aMoieties

In a different embodiment of section 2.1, additional preferred compoundshave the structures of formula IIbb

wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.2.11a Additional Compounds of Formula IIbb which Exemplify MorePreferred X2-E1 Moieties In an embodiment of section 2.11, preferredcompounds have the structures of formula IIcc

2.11b Additional Compounds of Formula IIbb which Exemplify MorePreferred X2-E1 Moieties

In another embodiment of section 2.11, preferred compounds have thestructures of formula IIdd

wherein R16 is C1-C6alkyl, cyano, —CCH, fluorine or chlorine.2.12 Compounds of Formula IIa which Exemplify Additionally Preferred AMoieties

In a different embodiment of section 2.1, additional preferred compoundshave the structures of formula IIee

wherein Q1 and Q2 individually and independently taken from the groupconsisting of N and CH;and wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.2.12a Additional Compounds of Formula IIee which Exemplify MorePreferred X2-E1 Moieties

In an embodiment of section 2.12 preferred compounds have the structuresof formula IIff

2.12b Additional Compounds of Formula Iee which Exemplify More PreferredX2-E1 Moieties

In another embodiment of section 2.12, preferred compounds have thestructures of formula IIgg

wherein R16 is C1-C6alkyl, cyano, —CCH, fluorine or chlorine.2.13 Compounds of Formula IIa which Exemplify Additionally Preferred AMoieties

In a different embodiment of section 2.1, additional preferred compoundshave the structures of formula IIhh

and wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.2.13a Additional Compounds of Formula IIhh which Exemplify morePreferred X2-E1 Moieties

In an embodiment of section 2.13, preferred compounds have thestructures of formula IIii

2.13b Additional Compounds of Formula IIhh which Exemplify MorePreferred X2-E1 Moieties

In another embodiment of section 2.13, preferred compounds have thestructures of formula IIjj

and wherein R16 is methyl, cyano, —CCH, fluorine or chlorine.2.14 Compounds of Formula IIa which Exemplify Additionally Preferred AMoieties

In a different embodiment of section 2.1, additional preferred compoundshave the structures of formula IIkk

wherein Q6 is N or C-A1;wherein A1 is selected from the group consisting of hydrogen,Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl,Z2-substituted C1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fullyor partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;and wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.2.14a Additional Compounds of Formula IIkk which Exemplify MorePreferred X2-E1 Moieties

In an embodiment of section 2.14, preferred compounds have thestructures of formula IIll

2.14b Additional Compounds of Formula IIkk which Exemplify MorePreferred X2-E1 Moieties

In another embodiment of section 2.14, preferred compounds have thestructures of formula IImm

wherein R16 is C1-C6alkyl, cyano, —CCH, fluorine or chlorine.2.15 Compounds of Formula IIa which Exemplify Additionally Preferred AMoieties

In a different embodiment of section 2.1, additional preferred compoundshave the structures of formula Inn

wherein A1 is selected from the group consisting of hydrogen,Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl,Z2-substituted C1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fullyor partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;and wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.2.15a Additional Compounds of Formula IInn which Exemplify MorePreferred X2-E1 Moieties

In an embodiment of section 2.15, preferred compounds have thestructures of formula Ioo

2.15b Additional Compounds of Formula IInn which Exemplify MorePreferred X2-E1 Moieties

In another embodiment of section 2.15, preferred compounds have thestructures of formula IIpp

wherein R16 is C1-C6alkyl, cyano, —CCH, fluorine or chlorine.2.16 Compounds of Formula IIa which Exemplify Additionally Preferred AMoieties

In a different embodiment of section 2.1, additional preferred compoundshave the structures of formula IIqq

wherein Q3, Q4 and Q5 are selected from the group consisting of N-A1 andC-A1, and only one of Q3, Q4, or Q5 is N-A1;and wherein A1 is selected from the group consisting of hydrogen,Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl,Z2-substituted C1-C6alkyl, fluoroC1-C6alkyl wherein the alkyl is fullyor partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;and wherein R16 is C1-C6alkyl, cyano, —CCH, or halogen.2.16a Additional Compounds of Formula IIqq which Exemplify MorePreferred X2-E1 Moieties

In an embodiment of section 2.16, preferred compounds have thestructures of formula IIrr

2.16b Additional Compounds of Formula IIqq which Exemplify MorePreferred X2-E1 Moieties

In another embodiment of section 2.16, preferred compounds have thestructures of formula IIss

wherein R16 is C1-C6alkyl, cyano, —CCH, fluorine or chlorine.

2.17 Methods 2.17a Methods of Protein Modulation

The invention includes methods of modulating kinase activity of RAFkinases and other kinases in the RAS-RAF-MEK-ERK-MAP kinase pathwayincluding, but not limited to, A-Raf, B-Raf, and C-Raf. The kinases maybe wildtype kinases, oncogenic forms thereof, aberrant fusion proteinsthereof or polymorphs of any of the foregoing. The method comprises thestep of contacting the kinase species with compounds of the inventionand especially those set forth in sections 2.1-2.16. The kinase speciesmay be activated or unactivated, and the species may be modulated byphosphorylations, sulfation, fatty acid acylations glycosylations,nitrosylation, cystinylation (i.e. proximal cysteine residues in thekinase react with each other to form a disulfide bond) or oxidation. Thekinase activity may be selected from the group consisting of catalysisof phospho transfer reactions, kinase cellular localization, andrecruitment of other proteins into signaling complexes throughmodulation of kinase conformation.

2.17b Treatment Methods

The methods of the invention, especially those of sections 2.1-2.16,also include treating individuals suffering from a condition selectedfrom the group consisting of chronic myelogenous leukemia, acutelymphocytic leukemia, gastrointestinal stromal tumors,hypereosinophillic syndrome, glioblastomas, ovarian cancer, pancreaticcancer, prostate cancer, lung cancers, breast cancers, kidney cancers,cervical carcinomas, metastasis of primary solid tumor secondary sites,ocular diseases characterized by hyperproliferation leading to blindnessincluding various retinopathies including diabetic retinopathy andage-related macular degeneration, rheumatoid arthritis, melanomas, coloncancer, thyroid cancer, a disease caused by a mutation in theRAS-RAF-MEK-ERK-MAP kinase pathway, human inflammation, rheumatoidspondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septicshock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome,adult respiratory distress syndrome, stroke, reperfusion injury, neuraltrauma, neural ischemia, psoriasis, restenosis, chronic obstructivepulmonary disease, bone resorptive diseases, graft-versus-host reaction,Chron's disease, ulcerative colitis, inflammatory bowel disease,pyresis, and combinations thereof.

2.18 Pharmaceutical Preparations

The compounds of the invention, especially those of sections 2.1-2.16,may form a part of a pharmaceutical composition by combining one or moresuch compounds with a pharmaceutically acceptable carrier. Additionally,the compositions may include an additive selected from the groupconsisting of adjuvants, excipients, diluents, and stablilizers.

3. Synthesis of Compounds of the Present Invention

The compounds of Formulae Ia and IIa are prepared by the generalsynthetic methods illustrated in the Schemes below and the accompanyingexamples.

The compounds of general formula Ia, wherein the variables are asdefined above, can be prepared by general Scheme 1. Thus in step 1,reaction of amines of formula 1 with isocyanates of formula 2 providesureas of formula 5, examples of formula 1a. It will be understood thatthe isocyanates 2 may be either introduced into the reaction directly ormay be prepared in situ, for example, by the decomposition of acylazides (Curtius rearrangement) in the presence of 1. It will be furtherunderstood by those skilled in the art that certain carbamates, forexample trichloroethyl carbamates (3) and isopropenyl carbamates (4),also function as isocyanate equivalents and will find use in step 1.

Alternatively, when R3=H, amines of Formula 1 may be first converted toisocyanate equivalents 9 or 10 by reaction with trichloroethylchloroformate (7) or isopropenyl chloroformate 8), respectively. Furtherreaction of carbamates 9 or 10 with amine 11 provides ureas of formula12, a subset of Formula 1.

When R3 is not H, mono-R3-substituted ureas 5 and 12 may be converted todoubly-R3-substituted ureas as shown in Steps 4 and 5 of Scheme 1.Alkylation of the NH-ureas 5 or 12 with alkyl halides in the presence ofa base, for example potassium carbonate, Nail, potassium t-butoxide orBEMP, in a suitable solvent such as DMF provides compounds of formula 6,wherein the newly introduced R3 is alkyl or cycloalkyl. Alternatively,exposure of ureas 5 or 12 to copper(II) acetate and phenylboronic acids[See: Chan et. al, Tetrahedron Lett. 2003, 44, 3863-3865; Chan et. al,Tetrahedron Lett. 1998, 39, 2933-2936; Chan, D. M. T. Tetrahedron Lett.1996, 37, 9013-9016] provides the analogous compounds of formula 6wherein the newly incorporated R3 is phenyl.

A modified route to compounds of general formula Ia (16) is shown belowin Scheme 2. Thus, in step 1, compound 13 (equivalent to compound 5, 6or 12 wherein one of the Z6 groups is thiomethyl) can be oxidized to asulfoxide (14) or sulfone (15). Preferred reagents for suchtransformations include peroxybenzoic acids, oxone, oxaziridines, orother oxidants that will be recognized as standard oxidants of sulfuratoms by those skilled in the art. In practice, mixtures of 14 and 15are generally as effective as either 14 or 15 alone. Purification ofmixtures of 14 and 15 is not required prior to usage in step 2. In step2, the sulfoxide 14/sulfone 15 can be converted to a Z6-substitutedcompound 16 wherein the new Z6 moiety is attached to the pyrimidine ringwith a nitrogen atom linkage or an oxygen atom linkage by the contactingof 14/15 with an amine Z6-H (for example, NH(R4)₂) or a hydroxyl Z6-H(for example HOR4) respectively. Preferred solvents for suchtransformations include DMSO, DMF, THF, alcoholic solvents or neatHN(R4)₂ at temperatures ranging from 0° C. to 60° C.

The synthesis of various amines of Formula 1 is further described in thefollowing examples.

As indicated in Scheme 3, a suitable chloropyrimidine ester 17 isreacted with an R4-substituted amine (step 1) to provide compounds offormula 18. Preferred conditions for Scheme 3, step 1, include polarsolvents such as DMF, THF, acetonitrile, dioxane, water or mixturesthereof in the presence of optionally added bases such as triethylamineat temperatures between 0° C. and 100° C. As shown in step 2, reductionof ester 18 provides alcohol 19. Preferred reagents for thetransformation of step 2 include lithium aluminum hydride in THF attemperatures ranging from −78° C. to 50° C. As shown in step 3, aldehyde20 can be prepared by oxidation of alcohol 19 with oxidants such asmanganese dioxide.

In scheme 3 step 4, amino-aldehyde 20 can be converted into di-amine 22by a reductive amination with amine 21. Step 4 may be accomplished in aone-pot procedure by in-situ generation of an iminium ion in thepresence of a suitable reducing agent. Preferred conditions for thisone-pot variant of step 4 include the combination of aldehyde 20, amine21 and sodium triacetoxyborohydride in the presence of acetic acid ortrifluoroacetic acid at a temperature between 0 and 100° C. Thoseskilled in the art will recognize that equivalent two-pot proceduresexist for the transformation in step 4. For example, condensation ofamine 21 and aldehyde 20 to form a discrete Schiff base (imine, notshown) that can be isolated and purified by standard methods if desired.Subsequent reduction of said imine with reducing agents such as lithiumaluminumhydride then provides di-amines of formula 22.

In step 5, diamines 22 are reacted with phosgene or a phosgeneequivalent to provide cyclic ureas 23. Suitable phosgene equivalentsinclude diphosgene, triphosgene and carbonyldiimidazole. Preferredconditions for step 5 are contacting diamine 22 with diphosgene in thepresence of a tertiary amine base such as triethylamine ordiisopropylethylamine at a temperature between 0 and 100° C. Preferredsolvents for step 5 include dioxane or toluene.

In Scheme 3 step 6, the nitro group of 23 is reduced to provide amine24, an example of general amine 1. Preferred methods for step 6 includeexposure of compounds of formula 23 to hydrogen gas in the presence of asuitable hydrogenation catalyst, for example Pd on carbon in a suitablesolvent such as ethanol, ethyl acetate or THF. Other preferred methodsfor step 6 include reductions with powdered metal reagents, for exampleiron powder in the presence of aqueous HCl or zinc dust in the presenceof ammonium chloride.

In Scheme 3, step 7, the amino moiety of 24 can be optionally“alkylated” to provide an R3-substituted amine 25, also an example ofgeneral amine 1. Those skilled in the art will recognize that a varietyof standard synthetic methods exist for the transformation of step 7including direct alkylation with a reagent of formula R3-X (where X is aleaving group such as a halide or tosylate), reductive amination withR3-containing aldehydes, or a two-step process in which the amine isfirst acylated to provide an R3-containing amide, which can besubsequently reduced to provide an R3-alkylated compound 25.

In step 8, the thiomethyl moiety of 25 can be oxidized to a sulfoxide 26or sulfone 27. Preferred reagents for such transformations includeperoxybenzoic acids, oxone, oxaziridines, or other oxidants that will berecognized as standard oxidants of sulfur atoms by those skilled in theart.

In an analogous manner to Scheme 2, sulfoxide 26/sulfone 27 can beconverted to a Z6-substituted compound 28 (step 9) wherein the new Z6moiety is attached to the pyrimidine ring with a nitrogen atom linkageor an oxygen atom linkage by the contacting of 26/27 with an amine Z6-H[for example, NH(R4)₂] or a hydroxyl Z6-H (for example HOR4)respectively. Preferred solvents for such transformations include DMF,THF, DMSO, alcoholic solvents or neat NH(R4)₂ at temperatures rangingfrom 0° C. to 200° C., optionally in the presence of a base such aspotassium tert-butoxide, sodium hydride, hydroxide, or the like or,alternatively, in the presence of a strong acid such as hydrochloricacid. Those skilled in the art will recognize that in certain instances,compounds of formula 28 can be prepared directly from compounds offormula 25 using the conditions of step 9.

An alternate synthetic route to compounds of Formula 22 is shown inScheme 4. Thus, alcohol 19 can be converted to chloride 29 by the actionof thionyl chloride or phosphorus oxychloride (POCl₃). Reaction ofchloride 29 with amine 21 provides diamine 22. Preferred conditions forthe Scheme 4 step 2 transformation include contacting chloride 29 withamine 21 in the presence of diisopropylethylamine and optionally in thepresence of sodium iodide. Preferred solvents for step 2 includeacetonitrile and dioxane at temperatures between 0 and 80° C.

Those skilled in the art will recognize that the nitro moiety of amine21 in schemes 3 and 4 represents an amine surrogate and hence the nitroamine 21 may be replaced in schemes 3 and 4 with amine 30, below,wherein the group “P” in formula 30 represents an amine protectinggroup, such as tert-butyl carbamate (Boc), benzyl carbamate (Cbz),acetamide or the like. It will be understood by those skilled in the artthat when intermediate 30 is substituted in place of amine 21 in Scheme3, the protecting group P of formula 30 can be removed by appropriatedeprotection conditions (for example, acidic removal for a Boc orhydrogenation for a Cbz) to provide compounds leading to the productionof intermediate 25. It will be further understood by those skilled inthe art that the moiety R3-N—P—X2 in formula 30 might also represent anamino-X2 surrogate such as a cyano that can be converted to anaminomethyl group in an analogous manner by reduction under suitableconditions.

Non-commercially available pyrimidines 17 can be readily prepared fromknown intermediate 31 [See Seto, et al. Biorg, Med, Chem. Lett. 2005,15, 1485]. (Scheme 5) Thus, lithiation of 31 with LDA followed by CO₂quench provides acid 32. Conversion of acid 32 to ester 33 provides ascaffold to introduce Z6 groups of the invention. When the Z6 moiety isattached to the pyrimidine ring through a Z6 nitrogen atom, a Z6 oxygenatom or a Z6 sulfur atom, compounds of formula 17 can be prepared bycontacting the amine Z6-H, the alcohol Z6-H or the thiol Z6-H withcompound 33, either neat (Z6-H as solvent) or in a suitable solvent suchas DMF, DMSO or an alcoholic solvent at temperatures ranging from −78°C. to 200° C. in the presence of suitable base such as triethylamine,potassium carbonate, or potassium tert-butoxide. When the Z6 moiety isattached to the pyrimidine through a Z6 carbon atom, preferred methodsinclude contacting compound 33 with a species of formula Z6-M in thepresence of a palladium catalyst, wherein M is a species thatparticipates in transition-metal catalyzed cross-coupling reactions.Examples of suitable M groups include but are not limited to, boronicacids and boronic esters, zinc, copper, tin, silicon, magnesium,lithium, and aluminum.

Some amines of general formula 1 can also be prepared as shown in Scheme6. Thus, reaction of R4-substituted amines with5-bromo-2,6-dichloropyrimidine (34, commercially available) providesbromo amine 35. In step 2, treatment of bromides 35 withtributylvinyltin in the presence of a palladium catalyst provides 36. Instep 3, oxidative cleavage of the olefin moiety provides aldehydes offormula 37. Application of steps 4-7 of Scheme 3 converts aldehyde 37 toamine 38. In Scheme 6 step 8, chloride 38 can be converted toZ6-substituted 39 by several methods, depending on the nature of Z6.When the Z6 moiety is attached to the pyridopyrimidine ring through a Z6nitrogen atom, preferred methods include heating 38 with an excess ofthe amine Z6-H either neat or in a solvent such as DMF, DMSO or analcoholic solvent at temperatures ranging from room temp to 200° C. Forthe case of aryl and heteroaryl amines Z6-H, additional preferredmethods include the heating of compounds 38 with an excess of the amineZ6-H and an acid catalyst (for example, TsOH, HCl, HOAc or the like) ina suitable solvent such as DMF, DMSO or an alcoholic solvent. Additionalpreferred methods for aryl and heteroarylamines Z6-H include heatingwith 38 in the presence of a transition metal catalyst such as apalladium catalyst in a suitable solvent like 1,4-dioxane or DMF. Whenthe Z6 moiety is attached to the pyridopyrimidine through a Z6 oxygen orsulfur atom, preferred methods include heating 38 with alcohol or thiolZ6-H in the presence of a strong base (for example, NaH or potassiumtert-butoxide) either neat using Z6-H as the solvent, or in a polarsolvent such as DMF or DMSO at temperatures ranging from room temp to200° C. When the Z6 moiety is attached to the pyridopyrimidine through aZ6 carbon atom, preferred methods include contacting 38 with a speciesof formula Z6-M in the presence of a palladium catalyst, wherein M is aspecies that participates in transition-metal catalyzed cross-couplingreactions. Examples of suitable M groups include but are not limited to,boronic acids and boronic esters, zinc, trialkyltin, silicon, magnesium,lithium, and aluminum. In the instance that Z6 is hydrogen, preferredmethods include exposure of 38 to hydrogen gas in the presence of asuitable hydrogenation catalyst, for example Raney Nickel® or Pd oncarbon in a suitable solvent such as ethanol, ethyl acetate or THF.

Some compounds of Formula IIa can be prepared by the methods in Scheme7. By analogy to Scheme 1, amines 40 or 41 (wherein all variables are asdescribed above) are reacted with isocyanate 2) or isocyanate surrogatesuch as 3, 4 or an acyl azide via a Curtius rearrangement (not shown) toprovide ureas 42 and 43 respectively, examples of general Formula IIa.In the instances where R3=H, amines of Formula 40 and 41 may be firstconverted to isocyanate equivalents 44-47 by reaction withtrichloroethyl chloroformate (2) or isopropenyl chloroformate (8).Further reaction of carbamates 44-47 with amine 11 provides ureas offormula 48 and 49, examples of Formula IIa. When R3 is not H,mono-R3-substituted ureas 42, 43, 48, or 49 may be converted todoubly-R3-substituted ureas 50 or 51 as shown in Steps 4 and of Scheme 7by the methods described above in Scheme 1.

Amines of general formulae 40 and 41 are available by the followingschemes and accompanying experimental examples. Scheme 8 details thepreparation of general amine 60.

By analogy to Scheme 3, a Z6-substituted dichloronicotinic acid ethylester 52 is reacted with an R4-substituted amine (Scheme 8, step 1) toprovide compounds of formula 53. Preferred conditions for Scheme 8, step1, include polar solvents such as DMF, THF, acetonitrile, dioxane, wateror mixtures thereof in the presence of optionally added bases such astriethylamine at temperatures between 0° C. and 100° C. As shown in step2, reduction of ester 53 provides alcohol 54. Preferred reagents for thetransformation of step 2 include lithium aluminum hydride in THF attemperatures ranging from −78° C. to 50° C. As shown in step 3, aldehyde55 can be prepared by oxidation of alcohol 54 with oxidants such asmanganese dioxide.

In Scheme 8 step 4, amino-aldehyde 55 can be converted into di-amine 56by a reductive amination with amine 21. Step 4 may be accomplished in aone-pot procedure by in-situ generation of an iminium ion in thepresence of a suitable reducing agent. Preferred conditions for thisone-pot variant of step 4 include the combination of aldehyde 55, amine21 and sodium triacetoxyborohydride in the presence of acetic acid ortrifluoroacetic acid at a temperature between 0 and 100° C. Alternately,step 4 can be a two-pot procedure in which amine 21 and aldehyde 55 arefirst condensed to form a discrete Schiff base (imine, not shown) thatcan be isolated and purified by standard methods if desired. Subsequentreduction of said imine with reducing agents such as lithiumaluminumhydride then provides di-amines of formula 56. More preferably,56 can also be prepared from alcohol 54 via the corresponding chloride(not shown) according to the procedure described above for Scheme 4.

In step 5, diamines 56 are reacted with phosgene or a phosgeneequivalent to provide cyclic ureas 57. Suitable phosgene equivalentsinclude diphosgene, triphosgene and carbonyldiimidazole. Preferredconditions for step 5 are contacting diamine 56 with diphosgene in thepresence of a tertiary amine base such as triethylamine ordiisopropylethylamine at a temperature between 0 and 100° C. Preferredsolvents for step 5 include dioxane or toluene.

In Scheme 8 step 6, the nitro group of 57 is reduced to provide amine58. Preferred methods for step 6 include exposure of compounds offormula 57 to powdered metal reagents, for example iron powder in thepresence of aqueous HCl or zinc dust in the presence of ammoniumchloride. In step 7, the amino moiety of 58 can be optionally“alkylated” to provide an R3-substituted amine 59. Those skilled in theart will recognize that a variety of standard synthetic methods existfor the transformation of step 7 including direct alkylation with areagent of formula R3-X (where X is a leaving group such as a halide ortosylate), reductive amination with R3-containing aldehydes, or two-stepprocesses in which the with the amine is first acylated to provide anR3-containing amide, which can be subsequently reduced to provide anR3-alkylated compound 59.

Compounds of formula 59 can be converted to compounds of formula 60, anexample of general formula 40, by replacement of the chloride moiety of59 with a Z6 moiety (step 8).

There are several methods through which this can be accomplished,depending on the nature of the Z6-H. When the Z6 moiety is attached tothe pyridine ring through a Z6 nitrogen atom, preferred methods includeheating compounds of formula 59 with an excess of the amine Z6-H eitherneat or in a solvent such as DMF, DMSO or an alcoholic solvent attemperatures ranging from room temp to 200° C. For the case of aryl andheteroaryl amines Z6-H, additional preferred methods include the heatingof compound 59 with an excess of the amine Z6-H and an acid catalyst(for example, TsOH, HCl, HOAc or the like) in a suitable solvent such asDMF, DMSO or an alcoholic solvent. Additional preferred methods for aryland heteroarylamines Z6-H include heating with compound 59 in thepresence of a transition metal catalyst such as a palladium catalyst ina suitable solvent like 1,4-dioxane or DMF. When the Z6 moiety isattached to the pyridine through a Z6 carbon atom, preferred methodsinclude contacting compound 59 with a species of formula Z6-M in thepresence of a palladium catalyst, wherein M is a species thatparticipates in transition-metal catalyzed cross-coupling reactions.Examples of suitable M groups include but are not limited to, boronicacids and boronic esters, zinc, trialkyltin, silicon, magnesium,lithium, and aluminum. In the instance that Z6 is hydrogen, preferredmethods include exposure of compounds of formula 59 to hydrogen gas inthe presence of a suitable hydrogenation catalyst, for example Pd oncarbon in a suitable solvent such as ethanol, ethyl acetate or THF.

A preferred method for preparing amines of general Formula 40 in whichthe pyridine ring Z6 substituent is aminomethyl is illustrated in Scheme9 with the preparation of general amine 66. Thus, chloropyridine 61(prepared from ethyl 2,4-dichloronicotinate by analogy to Scheme 8,step 1) undergoes reaction with N,O-dimethylhydroxylamine HCl to provideaminopyridine ester 62 (step 1). The ester 62 can be reduced to alcohol63 as described above. In step 3, alcohol 63 is converted to diamine 64following the protocols described in Scheme 4 above. Treatment of 64with diphosgene as described above provides the cyclic urea 65.Concomitant reduction of the nitro group and cleavage of themethoxyamine N—O bond in Scheme 9 step 5, provides 66, an example ofgeneral amine 40. Preferred conditions for step 5 include exposing 65 tohydrogen gas in the presence of a suitable hydrogenation catalyst, forexample Pd on carbon, in a suitable solvent such as methanol, ethanol,ethyl acetate or THF at a pressure of 1-100 psi and a temperature of15-80° C.

Amines of general formula 41 can be prepared as shown in Scheme 10.Starting with 3-bromo-2,6-dichloropyridine (67, available by theprocedure of Pierrat et al. J. Comb. Chem. 2005, 7, 879-886), reactionof R4-substituted amines provides bromo amine 68. In step 2, treatmentof bromide 68 with tributylvinyltin in the presence of a palladiumcatalyst provides 69, and then by analogy to Scheme 6, amine 71 can beprepared as an example of general amine 41.

Amines of formula 1 wherein X—Y is C═N can be prepared as outlined inScheme 11. Thus, in step 1, selective displacement of one of thechlorine atoms in dichloro-nitropyrimidines 72 (Z6=H, Z6=methyl,Z6=carboxyethyl are commercially available) can be accomplished bytreatment with R4-substituted amines in an appropriate solvent such asTHF at a temperature between −78° C. and room temp to provide compounds73. In step 2, replacement of the remaining chlorine atom with a Z6moiety can be accomplished by the method discussed above in Scheme 6step 8 to provide compound 74. Reduction of the nitro group provides adiamine of formula 75 (step 3). Condensation of compounds 75 withalpha-ketoesters of formula 76 in step 4 provides compounds of formula77. In step 5, the optional protecting group P is removed to providecompounds 78, an example of amine 1.

By analogy to Scheme 11, examples of amines 40 and 41 wherein X—Y is C═Ncan be prepared as shown in Scheme 12. In step 1, reaction ofdichloro-nitropyridines 79 (Z6=H: See Recueil des Travaux Chimiques desPays-Bas, 1976, 95, 127-129) and 80 (Z6=H: commercially available) withR4-substituted amines in an appropriate solvent such as THF providescompounds 81 and 82 respectively. In step 2, replacement of theremaining chlorine atom with a Z6 moiety can be accomplished by themethod discussed above in Scheme 6 step 8 to provide compounds 83-84. Byanalogy to Scheme 11, steps 3-5, nitroamines 83 and 84 can be convertedto 85 and 86, examples of amines 40 and 41 respectively.

General method A: To a solution of the starting pyrazole amine (1 eq) inEtOAc were added 2,2,2-trichloroethylchloroformate (1.1 eq) andsaturated NaHCO₃ (2-3 eq) at 0° C. After stirring for 3 h at RT, thelayers were separated and the aqueous layer extracted with EtOAc. Thecombined organic extracts were washed with brine, dried (Na₂SO₄) andconcentrated in vacuo to yield the crude TROC carbamate of the pyrazoleamine. To the carbamate (1 eq) in DMSO were added diisopropylethylamine(2 eq), the appropriate amine (2 eq) and the mixture was stirred at 60°C. for 16 h or until all the starting carbamate was consumed. Water wasadded to the mixture and the product was extracted with EtOAc (2×25 mL).The combined organic extracts were washed with brine solution, dried(Na₂SO₄) and concentrated in vacuo to yield crude product, which waspurified by column chromatography to yield the target compound.

General method B: To a suspension of the amine (usually 0.67 mmol) inEtOAc (2 mL) was added aqueous 1N NaOH. The reaction mixture was cooledto 0° C. and treated with isopropenyl chloroformate (0.1 mL, 0.94 mmol)over 30 sec. The reaction mixture was stirred 15 min at 0° C. and 1 h atRT. The reaction was poured into THF-EtOAc (1:1; 40 mL) and washed withH₂O (2×10 mL) and brine (2×10 mL). The organics were dried (Na₂SO₄),concentrated in vacuo and the residue purified via column chromatographyto provide the target (prop-1-en-2-yl)carbamate. To the carbamate(usually 0.26 mmol) was added the appropriate amine (usually 0.26 mmol)in THF (2 mL) and 1-methylpyrrolidine (Catalytic amount) at 60° C. for18 h. The mixture was diluted with CH₂Cl₂ (2 mL) and hexane (0.5 mL)solution, and stirred for 10 min. The resultant solid was filtered anddried and the resulting solid converted to the amine hydrochloride saltby treatment with 0.1 N HCl solution and lyophilization.

General Method C: To a stirring solution of amine (2 mmol, 1.00 eq) andpyridine (4 mmol, 2.00 eq) in CH₂Cl₂ (18 ml) at RT was added Troc-Cl(1.87 mmol, 1.05 eq). After 4 hours the reaction was washed with 3M HCl(1×), satd. NaHCO₃ (1×), dried (Na₂SO₄), filtered and evaporated toafford the target 2,2,2-trichloroethyl carbamate. The material was usedas is in the next reaction.

The 2,2,2-trichloroethyl carbamate (0.7 mmol, 1.00 eq), the appropriate(0.7 mmol, 1.00 eq) and iPr₂NEt (1.54 mmol, 2.20 eq) were combined inDMSO (3 ml) and stirred with heating at 70° C. After 18 h, the completedreaction was diluted with brine (30 ml) and extracted with EtOAc (3×).The combined organics were washed with brine (2×), dried (MgSO₄),filtered and evaporated to give the crude product which was purified viaflash column chromatography.

General Method D: To a stirring solution of carboxylic acid (0.50 mmol,1.00 eq) and DPPA (0.75 mmol, 1.50 eq) in 1,4-dioxane (5.0 ml) at RT wasadded Et₃N (1.5 mmol, 3.00 eq). After stirring for 30 min at RT, theappropriate amine (0.76 mmol, 1.50 eq) was added and the mixture washeated at 100° C. After 2 h, the completed reaction was cooled to RT,diluted with brine and extracted with EtOAc (2×). The combined organicswere washed with 3M HCl (1×), satd. NaHCO₃ (2×), and brine (1×), dried(MgSO₄), filtered and evaporated to give the crude product which waspurified by flash column chromatography to afford the target urea.

General Method E: To a solution of aryl sulfone and/or aryl sulfoxide(0.4 mmol) in THF was added the appropriate amine (2 mmol, 5 eq) and thereaction was stirred for 2 h at RT. The mixture was diluted with EtOAc(3 mL) and resultant solid filtered, washed and dried to provide thedesired product aryl amine.

General Method F: To a stirring suspension of isocyanate (0.51 mmol,1.00 eq) and pyridine (0.0418 ml, 0.51 mmol, 1.00 eq) in CH₂Cl₂ (5 ml)at RT was added the appropriate amine (0.51 mmol, 1.00 eq). A thicksuspension gradually formed. After 3.5 h, the solids were collected byfiltration, rinsed well with CH₂Cl₂ and dried on the filter to affordthe desired urea.

General Method G: To a solution of amine (11 mmol) in TI-F (100 mL) wasadded LiHMDS (22 mmol) at −78° C. under Ar. After 20 min, prop-1-en-2-ylchloroformate (11 mmol) was added and the reaction was stirred for 30min. The mixture was quenched with 2N HCl (15 mL) at −78° C. and warmedto RT. It was diluted with brine (50 mL) and EtOAc (50 mL), the organiclayer was separated and washed with brine, dried (Na₂SO₄) andconcentrated in vacuo. Purification by silica gel chromatography orrecrystallization provided the appropriate prop-1-en-2-yl carbamate.

To the carbamate (usually 0.26 mmol) was added the appropriate amine(usually 0.26 mmol) in THF (2 mL) and 1-methylpyrrolidine (Catalyticamount) at 60° C. for 18 h. The mixture was diluted with CH₂Cl₂ (2 mL)and hexane (0.5 mL) solution, and stirred for 10 min. The resultantsolid was filtered and dried and the resulting solid converted to theamine hydrochloride salt by treatment with 0.1 N HCl solution andlyophilization.

Example A1

Acetic acid (10 mL, 174 mmol) was added to a mixture of Example C2 (10g, 54.6 mmol) and 4-fluoro-3-nitroaniline (8.5 g, 54.6 mmol) in water(350 mL) and the mixture was stirred at RT overnight. The solid wascollected by filtration and washed with MeOH (2×20 mL) to give5-((4-fluoro-3-nitrophenylimino)methyl)-N-methyl-2-(methylthio)pyrimidin-4-amine(8.0 g, 46% yield) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆): δ 9.39(m, 1H), 8.71 (s, 1H), 8.33 (s, 1H), 8.18 (m, 1H), 7.80 (m, 1H), 7.61(t, J=6.9 Hz, 1H), 3.05 (d, J=3.6 Hz, 3H), 2.48 (s, 3H); MS (ESI) m/z:322.2 (M+H⁺).

To a suspension of LiAlH₄ (1.3 g, 34 mmol) in anhydrous THF at 0° C. wasadded the above5-((4-fluoro-3-nitrophenylimino)methyl)-N-methyl-2-(methylthio)pyrimidin-4-amineportionwise over 20 min. After the addition was complete, the mixturewas stirred at 0° C. for 30 min. Aqueous 10% NaOH (2 mL) was added andthe resultant precipitate was removed by filtration. The filtrate wasconcentrated under reduced pressure to give5-((4-fluoro-3-nitrophenylamino)methyl)-N-methyl-2-(methylthio)pyrimidin-4-amine(6.0 g, 56% yield) as a brown solid. ¹H NMR (300 MHz, DMSO-d₆): δ 7.84(s, 1H), 7.28 (dd, J=6.6, 8.4 Hz, 1H), 7.17 (m, 1H), 7.03 (m, 1H), 6.42(t, J=3.9 Hz, 1H), 4.00 (d, J=3.9 Hz, 2H), 2.82 (d, J=4.8 Hz, 3H), 2.39(s, 3H); MS (ESI) m/z: 324.1 (M+H⁺).

To a solution of diphosgene (3.5 g, 17.7 mmol) in dioxane (350 mL) at 0°C. was slowly added a solution comprised of5-((4-fluoro-3-nitrophenylamino)methyl)-N-methyl-2-(methylthio)pyrimidin-4-amine(5.2 g, 16.1 mmol) and Et₃N (4.5 mL, 32.1 mmol) in dioxane (250 mL). Theresultant reaction mixture was stirred at RT overnight. The solvent wasremoved in vacuo and the residue was partitioned between EtOAc and H₂O.The combined organics were dried (Na₂SO₄) and concentrated to give crudeproduct, which was washed with cold MeOH (5 mL) to give3-(4-fluoro-3-nitrophenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(5.0 g, 89% yield) as a brown solid. ¹H NMR (300 MHz, DMSO-d₆): δ 8.26(s, 1H), 8.20 (m, 1H), 7.82 (m, 1H), 7.64 (dd, J=6.9, 8.4 Hz, 1H), 4.82(s, 2H), 3.29 (s, 3H), 2.50 (s, 3H); MS (ESI) m/z: 350.3 (M+H⁺).

To a solution of3-(4-fluoro-3-nitrophenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(3.0 g, 8.6 mmol) in MeOH (30 mL) was added 10% Pd/C (1.2 g, 1.1 mmol).The resultant mixture was stirred overnight under H₂ (30 psi). Themixture was filtered, concentrated in vacuo and purified by silica gelcolumn chromatography to give3-(3-amino-4-fluorophenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(1.8 g, 66% yield) as a brown solid. ¹H NMR (300 MHz, DMSO-d₆): δ 8.21(s, 1H), 6.99 (dd, J=6.6, 8.4 Hz, 1H), 6.70 (dd, J=1.8, 6.0 Hz, 1H),6.47 (m, 1H), 5.21 (br s, 2H), 4.65 (s, 2H), 3.26 (s, 3H), 2.50 (s, 3H);MS (ESI) m/z: 320.0 (M+H⁺).

Example A2

To a solution of Example A1 (400 mg, 1.3 mmol) in CH₂Cl₂ (5 mL) wasadded 3-chloroperoxybenzoic acid (mCPBA) (430 mg, 2.5 mmol) in oneportion. After stirring for 2 h, the reaction mixture was quenched withaq NaHCO₃ and aq NaHSO₃. The organic layer was separated and was washedwith brine, dried (Na₂SO₄) and concentrated in vacuo. The crude productwas dissolved in DMSO (2 mL) and was treated with a solution of ammoniain dioxane (2 M, 30 ml, 60 mmol). The mixture stirred overnight at RT.The reaction was concentrated under reduced pressure and the residue waspurified by silica gel chromatography to provide7-amino-3-(3-amino-4-fluorophenyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(H)-one(276 mg, 77% yield) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆): δ 7.88(s, 1H), 6.96 (dd, J=8.4, 6.6 Hz, 1H), 6.68 (dd, J=6.3, 2.1 Hz, 1H),6.52 (br s, 2H), 6.44 (m, 1H), 5.18 (s, 2H), 4.48 (s, 2H), 3.19 (s, 3H);MS (ESI) m/z: 289.2. (M+H⁺).

Example A3

Example A1 (1.0 g, 3.1 mmol), mCPBA (1.1 g, 6.3 mmol) and methylaminewere combined by the procedure of Example A2 to provide3-(3-amino-4-fluorophenyl)-1-methyl-7-(methylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(370 mg, 39% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 7.93(s, 1H), 6.99-6.94 (m, 2H), 6.69 (d, J=8.4 Hz, 1H), 6.44 (m, 1H), 5.18(s, 2H), 4.50 (s, 2H), 3.23 (s, 3H), 2.78 (d, J=4.0 Hz, 3H); MS (ESI)m/z: (M+H⁺) 303.2

Example A4

POCl₃ (5.86 g, 38.6 mmol) was added dropwise to a solution of Example C3(3.8 g, 19.3 mmol) in THF (25 mL) at 0° C. The resulting mixture wasallowed to warm to 25° C. for 4 h. The solvent was removed under reducedpressure to give crude5-(chloromethyl)-N2-methoxy-N2,N4-dimethylpyridine-2,4-diamine HCl (3.5g, 84% yield), which was used in the next step without furtherpurification.

A mixture of the above5-(chloromethyl)-N2-methoxy-N2,N4-dimethylpyridine-2,4-diamine HCl (3.5g, 16.3 mmol) and 4-fluoro-3-nitroaniline (41.5 mL, 0.3 mol) in pyridine(150 mL) was stirred at 50° C. for 8 h. The reaction mixture wasconcentrated in vacuo to afford a crude product which was washed withH₂O and dried to give5-((4-fluoro-3-nitrophenylamino)methyl)-N2-methoxy-N2,N4-dimethylpyridine-2,4-diamine(3.3 g, 60% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 7.83 (m, 1H), 7.62 (s,1H), 7.30 (t, J=9.2 Hz, 1H), 7.20 (m, 1H), 6.98 (m, 1H), 6.81 (s, 1H),5.98 (s, 1H), 4.14 (s, 2H), 3.69 (s, 3H), 3.30 (s, 3H), 2.89 (d, J=4.8Hz, 3H); MS (ESI) m/z: 336.2 (M+W)

To a solution of diphosgene (1.15 mL, 9.5 mmol) in anhydrous dioxane(100 mL) was added a mixture of5-((4-fluoro-3-nitrophenylamino)methyl)-N2-methoxy-N2,N4-dimethylpyridine-2,4-diamine(3.0 g, 9.0 mmol) and Et₃N (2.5 mL, 18.0 mmol) in dioxane (200 mL) at10° C. After addition, the resulting mixture was stirred at 30° C. for10 h. H₂O was added to quench the above reaction and the mixture wasneutralized to pH 7 with saturated Na₂CO₃ solution. The dioxane wasremoved under reduced pressure and the remaining aqueous solution wasextracted with EtOAc (3×50 mL). The combined organics were washed withbrine, dried over MgSO₄ and concentrated to give3-(4-fluoro-3-nitrophenyl)-7-(methoxy(methyl)amino)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(2.1 g, 65% yield), which was used in the next step without furtherpurification. ¹H NMR (300 MHz, DMSO-d₆): δ 8.15 (m, 1H), 7.97 (s, 1H),7.80 (m, 1H), 7.62 (t, J=9.3 Hz, 1H), 6.58 (s, 1H), 4.80 (s, 2H), 3.72(s, 3H), 3.27 (s, 3H), 3.15 (s, 3H); MS (ESI) m/z: 362.2 (M+H⁺).

A solution3-(4-fluoro-3-nitrophenyl)-7-(methoxy(methyl)amino)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(2 g, 5.5 mmol) in methanol (30 mL) was stirred with 10% Pd/C (1.0 g,0.94 mmol) under hydrogen (45 psi) at 45° C. for 24 h. The completereaction mixture was filtered, and the filtrate was concentrated invacuo. The residue was washed with ethyl ether and dried in vacuo toprovide3-(3-amino-4-fluorophenyl)-1-methyl-7-(methylamino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(1.1 g, 66% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 7.70 (s, 1H), 6.94 (t,J=9.6 Hz, 1H), 6.66 (d, J=6.8 Hz, 1H), 6.40 (m, 2H), 5.92 (s, 1H), 5.17(s, 2H), 4.50 (s, 2H), 3.13 (s, 3H), 2.73 (d, J=4.0 Hz, 3H), MS (ESI)m/z: 302.1 (M+H⁺).

Example A5

n-Butyllithium (1.6 M in hexane, 109 mL, 0.175 mol) was added dropwiseto a −78° C. solution of 1-bromo-4-fluoro-2-methylbenzene (30 g, 0.16mol) in THF (500 mL) under N₂. After complete addition, the reactionmixture was stirred for 1 h at −78° C. The bright yellow solution wasquickly cannulated to another flask containing a pre-cooled (−78° C.)solution of diethyl oxalate (27.8 g, 0.19 mol) in THF (400 mL). Afterstirring for another 30 min at −78° C., the reaction mixture wasquenched by the addition of saturated NH₄Cl solution (800 mL). Theaqueous layer was extracted with EtOAc (3×400 mL) and the combinedorganics were dried (Na₂SO₄), concentrated in vacuo and purified viasilica gel chromatography to provide ethyl2-(4-fluoro-2-methylphenyl)-2-oxoacetate (22.0 g, yield, 66% yield). ¹HNMR (400 MHz, CDCl₃): δ 7.73 (dd, J=9.2, 5.6 Hz, 1H), 7.02-6.96 (m, 2H),4.40 (m, 2H), 2.60 (s, 3H), 1.29 (t, J=6.8 Hz, 3H). MS (ESI) m/z: 233.0[M+Na]⁺.

HNO₃ (6.92 g, 71.4 mmol) was added dropwise to a suspension of ethyl2-(4-fluoro-2-methylphenyl)-2-oxoacetate (15 g, 71.4 mmol) in conc.H₂SO₄ (50 mL) at ° C. After complete addition the resulting mixture wasstirred at 0° C. for 30 min. The mixture was poured into ice water, andextracted with EtOAc. The organic extract was washed with brine, dried(MgSO₄) and concentrated in vacuo to give ethyl2-(4-fluoro-2-methyl-5-nitrophenyl)-2-oxoacetate (15 g, 83% yield),which was used in the next step without further purification. ¹H NMR(400 MHz, CDCl₃): δ 8.53 (d, J=7.2 Hz, 1H), 7.24 (d, J=7.2 Hz, 1H), 4.47(q, J=7.2 Hz, 2H), 2.67 (s, 3H), 1.43 (t, J=7.2 Hz, 3H).

A mixture of ethyl 2-(4-fluoro-2-methyl-5-nitrophenyl)-2-oxoacetate (15g, 59 mmol) and Fe (46 g, 828 mmol) in AcOH (200 mL) was stirred at RTovernight. The solid was removed by filtration, and the solvent wasremoved under reduced pressure. The residue was partitioned with waterand EtOAc. The organic layer was washed with brine, dried (MgSO₄), andconcentrated in vacuo to give ethyl2-(5-amino-4-fluoro-2-methylphenyl)-2-oxoacetate (9.0 g, 70% yield),which was used in the next step without further purification. ¹H NMR(400 MHz, CDCl₃): δ 7.16 (d, J=6.9 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 4.41(q, J=7.2 Hz, 2H), 2.50 (s, 3H), 1.40 (t, J=7.2 Hz, 3H).

Acetyl chloride (3.12 g, 40 mmol) was added to a 0° C. solution of ethyl2-(5-amino-4-fluoro-2-methylphenyl)-2-oxoacetate (9 g, 40 mmol) and Et₃N(8.1 g, 80 mmol) in CH₂Cl₂ (80 mL). The resulting mixture was stirred atRT for 3 h. The solvent was removed under reduced pressure to give ethyl2-(5-acetamido-4-fluoro-2-methylphenyl)-2-oxoacetate (10.7 g, 100%yield), which was used in the next step without further purification. ¹HNMR (300 MHz, CDCl₃): δ 8.71 (d, J=6.0 Hz, 1H), 7.37 (brs, 1H), 6.95 (d,J=8.7 Hz, 1H), 4.39 (q, J=7.2 Hz, 2H), 2.50 (s, 3H), 2.10 (s, 3H), 1.40(t, J=7.2 Hz, 3H).

A mixture of ethyl 2-(5-acetamido-4-fluoro-2-methylphenyl)-2-oxoacetate(5 g, 19 mmol), Example D3 (5.7 g, 38 mmol) and AcOH (2 mL) in EtOH (100mL) was charged in steel bomb and heated at 100° C. for 48 h. Thesolvent was removed under reduced pressure and the residue was purifiedby column chromatography to giveN-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropteridin-6-yl)phenyl)acetamide(1.5 g, 23% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.71 (br s, 1H), 8.66(s, 1H), 8.00 (s, 1H), 7.87 (m, 1H), 7.16 (d, J=11.2 Hz, 1H), 3.58 (s,3H), 2.93 (s, 3H), 2.18 (s, 3H), 2.06 (s, 3H); MS (ESI) m/z: 357.2[M+H]⁺.

A solution ofN-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropteridin-6-yl)phenyl)acetamide(1.5 g, 4.2 mmol) and conc. HCl (1 mL) in MeOH (20 mL) was heated atreflux overnight. The solvent was removed under reduced pressure. Waterwas added, and the mixture basified to pH=8. The resulting precipitatewas collected by filtration and dried to give6-(5-amino-4-fluoro-2-methylphenyl)-8-methyl-2-(methylamino)pteridin-7(8H)-one(1.0 g, 78% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.70 (s, 0.3H), 8.62(s, 0.7H) □ 7.96 (m, 0.7H) □ 7.85 (m, 0.3H) □ 6.88 (d, J=12.4 Hz, 1H),6.78 (d, J=9.2 Hz, 1H), 4.98 (s, 2H), 3.56 (s, 2H), 3.48 (s, 1H) □ 2.91(d, J=4 Hz, 3H), 2.03 (s, 3H). MS (ESI) m/z: 315.2 [M+H]⁺.

Example A6

Sodium triacetoxy borohydride (2.70 g, 12.8 mmol) was added to asolution of Example C5 (2.10 g, 10.6 mmol), 4-fluoro-3-nitroaniline(1.66 g, 10.6 mmol) and TFA (2.43 g, 21.3 mmol) in EtOAc (50 mL). Afterstirring for 30 min. the reaction mixture was diluted with water (50mL), and 2N NaOH was added to adjust the pH to alkaline. The organicphase was separated, washed with brine, dried (MgSO₄) and concentratedto give yellow orange solid. The solid was slurried in MTBE, collectedby filtration, washed and dried in vacuo to giveN-ethyl-5-((4-fluoro-3-nitrophenylamino)methyl)-2-(methylthio)pyrimidin-4-amine(2.2 g, 61% yield) as a bright yellow solid.

To a suspension ofN-ethyl-5-((4-fluoro-3-nitrophenylamino)methyl)-2-(methylthio)pyrimidin-4-amine(2.20 g, 6.5 mmol) in CH₂Cl₂ (25 mL) was added Et₃N (2.7 mL, 20 mmol)followed by phosgene (20% solution in toluene, 4.3 mL, 7.8 mmol). Thereaction mixture was stirred for 2 h at RT and then diluted with water.The organic layer was separated and washed with brine, dried (MgSO₄) andconcentrated to provide an orange yellow solid, which on stirring inethyl acetate followed by filtration provided1-ethyl-3-(4-fluoro-3-nitrophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-oneas a light yellow solid.

To a solution of1-ethyl-3-(4-fluoro-3-nitrophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(2.4 g, 6.5 mmol) in ethyl acetate and methanol (1:1, 40 mL) was addedPd/C (230 mg) and the mixture was hydrogenated (55 psi) in a Parr shakerfor 2 days. The reaction mixture was filtered and the filter cake waswashed with methanol. The combined filtrates were concentrated in vacuo.The residue was dissolved in THF and the solid was filtered. Thefiltrate was concentrated and purified by silica gel columnchromatography to obtain3-(3-amino-4-fluorophenyl)-1-ethyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(0.65 g, 30% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.20 (s, 1H), 6.97 (m,1H), 6.70 (dd, J=8.0, 2.4 Hz, 1H), 6.46 (m, 1H), 5.21 (s, 2H), 4.64 (s,2H), 3.94 (q, J=6.8 Hz, 2H), 2.48 (s, 3H), 1.15 (t, J=6.8 Hz, 3H); MS(ESI) m/z: 334.1 (M+H⁺).

Example A7

Using a procedure analogous to Example A2, Example A6 (0.65 g, 1.9 mmol)was treated with mCPBA (70% wt, 0.58 g, 2.3 mmol) and then N-methylamine(2.0M in THF, 3.9 mL, 7.8 mmol) to afford3-(3-amino-4-fluorophenyl)-1-ethyl-7-(methylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(1.79 g, 94% yield). ¹H NMR (400 MHz, DMSO-d₆, major tautomer): δ 8.00(s, 1H), 7.04 (m, 2H), 6.76 (dd, J=8.4, 2.8 Hz, 1H), 6.52 (m, 1H), 5.27(s, 2H), 4.57 (s, 2H), 3.99 (q, J=6.4 Hz, 2H), 2.84 (d, J=4.8 Hz, 3H),1.22 (t, J=6.4 Hz, 3H); MS (ESI) m/z: 317.0 (M+H⁺).

Example A8

To a solution of Example A1 (700 mg, 2.2 mmol) in THF (10 mL) was addedRaney-Ni (50% wt slurry in water, 1.0 g) and then the reaction mixturewas stirred under 1 atm of Hi at 60° C. for 5 h. The mixture wasfiltered through diatomite and the cake was washed with THF. Thecombined filtrate was concentrated to give3-(3-amino-4-fluoro-phenyl)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one(460 mg, 76% yield) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆): δ 8.77(s, 1H), 8.39 (s, 1H), 6.99 (dd, J=11.4, 8.7 Hz, 1H), 6.72 (d, J=8.1 Hz,1H), 6.49 (m, 1H), 5.24 (br s, 2H), 4.73 (s, 2H), 3.28 (s, 3H). MS (ESI)m/z: 274.2 (M−H⁺).

Example A9

Using a procedure analogous to Example A10, Example C6 (7 g, 33 mmol)and 4-fluoro-3-nitrophenylamine (4.7 g, 30 mmol) were converted to3-(3-amino-4-fluorophenyl)-1-isopropyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(2 g). ¹H NMR (400 MHz, DMSO-d₅): δ 8.23 (s, 1H), 6.97 (m, 1H), 6.69(dd, J=8.4, 2.4 Hz, 1H), 6.44 (m, 1H), 5.22 (s, 2H), 4.94 (m, 1H), 4.59(s, 2H), 2.49 (s, 3H), 1.45 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 348.1[M+H]⁺.

Example A10

To a solution of Example C1 (10 g, 56 mmol) in anhydrous THF (120 mL)was added thionyl chloride (10.4 mL, 140 mmol) slowly at 0° C. Theresulting mixture was stirred at 80° C. for 4 hours. The solvent wasremoved under reduced pressure to give5-(chloromethyl)-N-methyl-2-(methylthio)pyrimidin-4-amine (11.5 g, >100%yield), which was used directly in the next step.

To a solution of5-(chloromethyl)-N-methyl-2-(methylthio)pyrimidin-4-amine (11.5 g) andExample D1 (9.6 g, 56 mmol) in anhydrous CH₃CN (160 mL) was added NaI(1.7 g, 11 mmol) and diisopropylethylamine (14.6 g, 112 mmol), then themixture was stirred at 60° C. overnight. After removing the solvent, theresidue was purified by column chromatography to give5-((4-fluoro-2-methyl-5-nitrophenylamino)methyl)-N-methyl-2-(methylthio)pyrimidin-4-amine(7 g, 37% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 7.83 (s, 1H), 7.22 (d,J=12 Hz, 1H), 7.08 (m, 1H), 6.98 (d, J=8 Hz, 1H), 5.79 (s, 1H), 4.09 (d,J=8 Hz, 2H), 2.85 (d, J=4 Hz, 3H), 2.37 (s, 3H), 2.17 (s, 3H); MS (EST)m/z: 337.9 [M+H]⁺.

To a solution of diphosgene (0.85 mL, 7.2 mmol) in anhydrous dioxane (20mL) was added a solution of5-((4-fluoro-2-methyl-5-nitrophenylamino)methyl)-N-methyl-2-(methylthio)pyrimidin-4-amine(2.2 g, 6.5 mmol) and Et₃N (1.32 g, 13 mmol) in anhydrous dioxane (50ml) at 0° C. After the addition, the resulting mixture was stirred at50° C. overnight. Water was added and the mixture was neutralized withsaturated Na₂CO₃ solution to pH 8. The dioxane was removed in vacuo, andthe aqueous layer was extracted with EtOAc (3×60 mL). The combinedorganics were washed with brine, dried (Na₂SO₄) and concentrated. Theresidue was washed with ether and dried in vacuo to afford3-(4-fluoro-2-methyl-5-nitrophenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(2 g, 84%). ¹H NMR (400 MHz, CDCl₃): δ 8.04 (s, 1H), 7.97 (d, J=8 Hz,1H), 7.18 (d, J=12 Hz, 1H), 4.73 (d, J=14.8 Hz, 1H), 4.42 (d, J=14.8 Hz,1H), 3.40 (s, 3H), 2.52 (s, 3H), 2.25 (s, 3H); MS (ESI) m/z: 364.1[M+H]⁺.

3-(4-fluoro-2-methyl-5-nitrophenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(3 g, 8.26 mmol) was added to a solution of HCl (1.6 g, 16.5 mmol) inEtOH (50 ml) followed by iron power (4.6 g, 80 mmol), and the resultingmixture was stirred at 50° C. for 6 hours. The mixture was filtered andthe filtrate was neutralized with saturated Na₂CO₃ solution to pH 8 andthe mixture was extracted with EtOAc (3×150 mL). The combined extractswere washed with brine, dried (Na₂SO₄) and evaporated to give3-(5-amino-4-fluoro-2-methylphenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(1.9 g, 67% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.19 (s, 1H), 6.89 (d,J=12.4 Hz, 1H), 6.65 (d, J=8.8 Hz, 1H), 5.01 (s, 2H), 4.62 (d, J=14.8Hz, 1H), 4.44 (d, J=14.8 Hz, 1H), 3.24 (s, 3H), 2.48 (s, 3H), 1.92 (s,3H); MS (ESI) m/z: 334.1 [M+H]⁺.

Example A11

Using the procedure of Example A9, steps 2-4, Example D1 (3.68 g, 22mmol) and 5-(chloromethyl)-N-isopropyl-2-(methylthio)pyrimidin-4-amine(5 g, 22 mmol) were combined to afford3-(5-amino-4-fluoro-2-methylphenyl)-1-isopropyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(1 g, 12% yield over 3 steps). ¹H NMR (400 MHz, DMSO-d₆): δ 8.23 (s,1H), 6.90 (d, J=12.0 Hz, 1H), 6.67 (d, J=8.8 Hz, 1H), 5.04 (s, 2H), 4.97(m, 1H), 4.60 (d, J=14.4 Hz, 1H), 4.40 (d, J=14.4 Hz, 1H), 2.50 (s, 3H),1.93 (s, 3H), 1.46 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 362.1 [M+H]⁺.

Example A12

solution of 3-amino-5-nitrobenzonitrile (3.59 g, 22 mmol) in CH₃CN (10mL) was added dropwise to a mixture of5-(chloromethyl)-N-isopropyl-2-(methylthio)pyrimidin-4-amine fromExample A9 (5 g, 22 mmol), sodium iodide (0.33 g, 2.2 mmol), anddiisopropylethylamine (2 mL, 12 mmol) in CH₃CN (100 mL) at 0° C. Theresultant reaction mixture was stirred at RT overnight. The solvent wasevaporated and the residue was diluted with water, and extracted withEtOAc. The combined organics were washed with brine, dried (MgSO₄),concentrated and purified by silca gel chromatography to afford3-((4-(isopropylamino)-2-(methylthio)pyrimidin-5-yl)methylamino)-5-nitrobenzonitrile(2.2 g, 28% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 7.87 (s, 1H), 7.74 (s,1H), 7.56 (s, 1H), 7.32 (s, 1H), 7.08 (m, 1H), 6.63 (d, J=7.6 Hz, 1H),4.30 (m, 1H), 4.15 (s, 2H), 2.50 (s, 3H), 1.17-1.15 (d, J=6.4 Hz, 6H);MS (ESI) m/z: 359.2 [M+H]⁺.

Diphosgene (5 mL, 41 mmol),3-((4-(isopropylamino)-2-(methylthio)pyrimidin-5-yl)methylamino)-5-nitrobenzonitrile(2.2 g, 6.15 mmol) and Et₃N (2.5 mL) were combined by the procedure ofExample A4 step 3 to give3-(1-isopropyl-7-(methylthio)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-5-nitrobenzonitrile(1.2 g, 51% yield), which was used in the next step without furtherpurification.

3-(1-Isopropyl-7-(methylthio)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-5-nitrobenzonitrile(1.2 g, 3.13 mmol), iron powder (1.75 g, 31 mmol) and cone HCl (0.5 ml,6 mmol) were combined in methanol (100 mL) by the procedure of ExampleA10, step 4, to provide3-amino-5-(1-isopropyl-7-(methylthio)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)benzonitrile(280 mg, 25% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.27 (s, 1H), 6.89 (m,1H), 6.86 (d, J=2.0 Hz, 1H), 6.76 (t, J=2.0 Hz, 1H), 5.73 (d, J=2.8 Hz,2H), 4.98 (m, 1H), 4.68 (s, 2H), 2.51 (s, 3H), 1.48 (d, J=6.8 Hz, 6H);MS (ESI) m/z: 355.1 [M+H]⁺.

Example A13

Using the procedure of Example A10, Example C4 (6.0 g, 30.2 mmol) andExample D1 (3.9 g, 23 mmol) were converted to3-(5-amino-4-fluoro-2-methyl-phenyl)-1-ethyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(2.5 g, 31% yield over 4 steps). ¹H NMR (400 MHz, DMSO-d₆): δ 8.28 (s,1H), 6.98 (d, J=12.0 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 5.11 (s, 2H), 4.72(d, J=14.4 Hz, 1H), 4.53 (d, J=14.4 Hz, 1H), 4.03 (m, 2H), 2.57 (s, 3H),2.01 (s, 3H), 1.22 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 348.2 [M+H]⁺.

Example A14

Using the procedure of Example A15 steps 2-4,5-(chloromethyl)-N-ethyl-2-(methylthio)pyrimidin-4-amine from ExampleA13 (2.4 g, 10.5 mmol) and Example D2 (2.0 g, 10.5 mmol) were combinedto afford3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(0.9 g, 26% yield over 3 steps). ¹H NMR (400 MHz, DMSO-d₆): δ 8.26 (s,1H), 7.31 (d, J=10.8 Hz, 1H), 6.87 (d, J=9.2 Hz, 1H), 5.51 (s, 2H), 4.68(d, J=14.4 Hz, 1H), 4.54 (d, J=14.4 Hz, 1H), 3.98 (m, 2H), 2.52 (s, 3H),1.18 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 367.9 [M+H]⁺.

Example A15

To a solution of Example C1 (2 g, 11 mmol) in anhydrous THF (120 mL) wasadded thionyl chloride (1.74 mL, 23 mmol) slowly at 0° C. The resultingmixture was stirred at 80° C. for 4 hours. The solvent was removed underreduced pressure to give5-(chloromethyl)-N-methyl-2-(methylthio)pyrimidin-4-amine (2.1 g) whichwas used directly in the next step.

To a solution of5-(chloromethyl)-N-methyl-2-(methylthio)pyrimidin-4-amine (2.1 g) andExample D2 (2 g, 11 mmol) in anhydrous CH₃CN (50 mL) was added NaI (0.32g, 2.2 mmol) and diisopropylethylamine (2.8 g, 22 mmol). The resultantmixture was stirred at 60° C. overnight. After the solvent was removed,the residue was washed with EtOAc (3×100 mL) and purified by columnchromatography to give5-((2-chloro-4-fluoro-5-nitrophenylamino)methyl)-N-methyl-2-(methylthio)pyrimidin-4-amine(1.2 g, 30% yield). ¹H NMR (400 MHz, DMSO-d₆): 7.86 (s, 1H), 7.70 (d,J=12 Hz, 1H), 7.23 (d, J=8 Hz, 1H), 7.16 (m, 1H), 6.33 (t, J=8 Hz, 1H),4.17 (d, J=8 Hz, 2H), 2.81 (d, J=8 Hz, 3H), 2.37 (s, 3H); MS (ESI) m/z:357.9 [M+H]⁺.

To a solution of diphosgene (2.1 mL, 6.8 mmol) in anhydrous dioxane (30mL) was added a solution of5-((2-chloro-4-fluoro-5-nitrophenylamino)methyl)-N-methyl-2-(tnethylthio)pyrimidin-4-amine(2.2 g, 6.2 mmol) and Et₃N (1.32 g, 13 mmol) in anhydrous dioxane (30mL) at 0° C. After complete addition, the resulting mixture was stirredat 50° C. overnight. Water was added and the mixture was basified withsaturated Na₂CO₃ solution. The mixture was concentrated in vacuo and theresidue was extracted with EtOAc (3×100 mL). The combined organic layerswere washed with brine, dried (Na₂SO₄) and concentrated in vacuo. Theresidual solid was washed with ether and dried to afford3-(2-chloro-4-fluoro-5-nitrophenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(1.4 g, 59%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.53 (d, J=8 Hz, 1H), 8.26(s, 1H), 8.08 (d, J=12 Hz, 1H), 4.82 (d, J=16 Hz, 1H), 4.57 (d, J=16 Hz,1H), 3.29 (s, 3H), 2.50 (s, 3H); MS (ESI) m/z: 384.1 [M+H]⁺.

To a solution of3-(2-chloro-4-fluoro-5-nitrophenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(1.4 g, 3.7 mmol) in EtOH (30 mL) was added conc. HCl (0.75 g, 9 mmol),followed by active iron power (2 g, 36 mmol). The reaction was stirredat 50° C. for 6 hours. The reaction was filtered and the filtrate wasdiluted with water and treated with saturated aq Na₂CO₃ solution untilpH 8. The aqueous mixture was extracted with EtOAc (3×80 mL). Thecombined extracts were dried (Na₂SO₄) and concentrated in vacuo to give3-(5-amino-2-chloro-4-fluorophenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(1.08 g, 84% yield). ¹H NMR (400 MHz, DMSO-d₅): δ 8.25 (s, 1H), 7.30 (d,J=11.2 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 5.50 (s, 2H), 4.66 (d, J=14.6Hz, 1H), 4.53 (d, J=14.6 Hz, 1H), 3.27 (s, 3H), 2.51 (s, 3H); MS (ESI)m/z: 354.3 [M+H]⁺.

Example A16

Thionyl chloride (3.7 mL, 51 mmol) was added dropwise to a 0° C.solution of Example C3 (4 g, 20.3 mmol) in anhydrous THF (20 mL). Theresultant mixture was stirred at 25° C. for 4 h. The solvent was removedunder reduced pressure to give5-(chloromethyl)-N2-methoxy-N2,N4-dimethylpyridine-2,4-diamine (3.9 g,89% yield), which was used in the next step without furtherpurification.

Using a procedure analogous to Example A4 steps 2-4,5-(Chloromethyl)-N2-methoxy-N2,N4-dimethylpyridine-2,4-diamine (3.9 g,18 mmol) and Example D1 (3.08 g, 18.1 mmol) were combined to give3-(5-amino-4-fluoro-2-methylphenyl)-1-methyl-7-(methylamino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(1.5 g, 29% yield over 3 steps). ¹H NMR (400 MHz, DMSO-d₆): δ 7.72 (s,1H), 6.90 (d, J=12.0 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H), 6.41 (m, 1H), 5.95(s, 1H), 5.02 (s, 2H), 4.52 (d, J=13.6 Hz, 1H), 4.33 (d, J=13.6 Hz, 1H),3.17 (s, 3H), 2.77 (d, J=4.8 Hz, 3H), 1.94 (s, 3H); MS (ESI) m/z: 316.2[M+H]⁺.

Example A17

Thionyl chloride (5.86 g, 23.8 mmol) was added dropwise to a 0° C.solution of Example C7 (2.9 g, 11.9 mmol) in anhydrous THF (30 mL). Theresulting mixture was stirred at 25° C. for 4 h. The solvent was removedunder reduced pressure to give5-(chloromethyl)-N4-isopropyl-N2-methoxy-N2-methylpyridine-2,4-diamine(2.7 g, 87% yield), which was used in the next step without furtherpurification.

A mixture of5-(chloromethyl)-N4-isopropyl-N2-methoxy-N2-methylpyridine-2,4-diamine(2.7 g, 11.1 mmol) and Example D1 (1.9 g, 11.1 mol) in pyridine (60 mL)was stirred at 50° C. for 8 h. The pyridine was removed under reducedpressure and the residue was purified by slica gel chromatography togive5-((4-fluoro-2-methyl-5-nitrophenylamino)methyl)-N4-isopropyl-N2-methoxy-N2-methylpyridine-2,4-diamine(3.0 g, 71.6% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 7.84 (s, 1H), 7.32(d, J=12.4 Hz, 1H), 7.16 (d, J=6.4 Hz, 1H), 6.22 (s, 1H), 6.00 (t, J=5.2Hz, 2H), 4.28 (d, J=5.2 Hz, 2H), 3.82 (m, 1H), 3.72 (s, 3H), 3.17 (s,3H), 2.27 (s, 3H), 1.27 (d, J=6.4 Hz, 6H).

Using the procedure of Example A4 step 3, diphosgene (1.3 g, 6.4 mmol),5-((4-fluoro-2-methyl-5-nitrophenylamino)methyl)-N4-isopropyl-N2-methoxy-N2-methylpyridine-2,4-diamine(2.0 g, 5.3 mmol) and Et₃N (2.2 g, 21.2 mmol) were reacted in dioxane togive3-(4-fluoro-2-methyl-5-nitrophenyl)-1-isopropyl-7-(methoxy(methyl)amino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(1.5 g, 70% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.18 (d, J=7.2 Hz, 1H),7.94 (s, 1H), 7.55 (d, J=12.4 Hz, 1H), 6.68 (s, 1H), 4.77 (d, J=116 Hz,1H), 4.45-4.37 (m, 2H), 3.71 (s, 3H), 3.13 (s, 3H), 2.14 (s, 3H), 1.46(t, J=6.4 Hz, 6H).

Using the procedure of Example A4 step 4, a mixture of3-(4-fluoro-2-methyl-5-nitrophenyl)-1-isopropyl-7-(methoxy(methyl)amino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(1.5 g, 3.7 mmol) and Pd/C (0.7 g) was hydrogenated (45 psi) in methanol(60 mL) at 45° C. to afford3-(5-amino-4-fluoro-2-methylphenyl)-1-isopropyl-7-(methylamino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(0.83 g, 65.0% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 7.72 (s, 1H), 6.87(d, J=12.4 Hz, 1), 6.61 (d, J=8.8 Hz, 1H), 6.35 (m, 1H), 6.13 (s, 1H),4.98 (s, 2H), 4.41-4.20 (m, 3H), 2.76 (d, J=4.8 Hz, 3H), 1.90 (s, 3H),1.45 (t, J=6.4 Hz, 6H); MS (ESI) m/z: 344.2. [M+H]⁺.

Example A18

2-Chloro-4-fluoro-5-nitro-phenylamine (1.4 g, 7.4 mmol) was added to asolution of5-(chloromethyl)-N2-methoxy-N2,N4-dimethylpyridine-2,4-diamine fromexample A16 (1.6 g, 7.4 mmol) in pyridine (30 mL) and the mixture wasstirred at 50° C. for 8 hours. The reaction mixture was concentratedunder reduced pressure and the solid residue was thoroughly washed withwater to give5-((2-chloro-4-fluoro-5-nitrophenylamino)methyl)-N2-methoxy-N2,N4-dimethylpyridine-2,4-diamine(1.5 g, 56% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.01 (s, 1H), 7.76 (d,J=8.4 Hz, 1H), 7.71 (s, 1H), 7.34 (d, J=8 Hz, 1H), 6.56 (m, 1H), 5.98(s, 1H), 4.36 (d, J=4 Hz, 2H), 3.71 (s, 3H), 3.31 (s, 3H), 2.91-2.92 (d,J=4 Hz, 3H); MS (ESI) m/z: 369.9 [M+H]⁺.

Diphosgene (0.6 ml, 4.8 mmol),5-((2-chloro-4-fluoro-5-nitrophenylamino)methyl)-N2-methoxy-N2,N4-dimethylpyridine-2,4-diamine(1.7 g, 4.6 mmol) and Et₃N (0.93 g, 9.2 mmol) were combined by theprocedure of Example A4, step 3 to afford3-(2-chloro-4-fluoro-5-nitrophenyl)-7-(methoxy(methyl)amino)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(1.5 g, 83% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.59 (d, J=8 Hz, 1H),8.15 (d, J=8 Hz, 1H), 8.04 (s, 1H), 6.66 (s, 1H), 4.94 (d, J=14 Hz, 1H),4.61 (d, J=14 Hz, 1H), 3.84 (s, 3H), 3.35 (s, 3H), 3.25 (s, 3H); MS(ESI) m/z: 396.1 [M+H]⁺.

3-(2-chloro-4-fluoro-5-nitrophenyl)-7-(methoxy(methyl)amino)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (1 g, 2.5 mmol), Pd/C (0.3 g) werecombined in MeOH (30 mL) and hydrogenated (45 psi) at 50° C. for 4 days.The catalyst was removed by filtration and the filtrate was concentratedin vacuo. The residual solid was washed with ethyl acetate and dried invacuo to give3-(5-amino-2-chloro-4-fluorophenyl)-1-methyl-7-(methylamino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(0.6 g, 71% yield). ¹H-NMR (400 MHz, DMSO-d): δ 7.71 (s, 1H), 7.26 (d,J=10.8 Hz, 1H), 6.78 (d, J=8.8 Hz, 1H), 6.41 (m, 1H), 5.94 (s, 1H), 5.43(s, 2H), 4.50 (d, J=13.6 Hz, 1H), 4.40 (d, J=13.6 Hz, 1H), 3.16 (s, 3H),2.76 (d, J=5.2 Hz, 3H); MS (ESI) m/z: 336.2 [M+H]⁺.

Example A19

Thionyl chloride (3.5 mL, 0.048 mol) was added dropwise to a solution ofExample C8 (5 g, 0.024 mol) in dry THF (50 mL) at 0° C. The resultingmixture was stirred at RT for 4 hours and concentrated in vacuo to give5-(chloromethyl)-N4-ethyl-N2-methoxy-N2-methylpyridine-2,4-diamine (5.4g, 98% yield), which was used in the next step without furtherpurification.

5-(Chloromethyl)-N4-ethyl-N2-methoxy-N2-methylpyridine-2,4-diamine (5.4g, 0.024 mol) and Example D1 (4 g, 0.024 mol) were combined according toExample A4 step 2 to provide5-((2-chloro-4-fluoro-5-nitrophenylamino)methyl)-N4-ethyl-N2-methoxy-N-2-methylpyridine-2,4-diamine(6 g, 70%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.66 (s, 1H), 7.25 (d, J=12 Hz,1H), 7.05 (d, J=6.4 Hz, 1H), 6.04 (s, 1H), 5.96 (m, 1H), 4.24 (d, J=8Hz, 2 H), 3.67 (s, 3H), 3.32 (q, J=8 Hz, 2H), 3.23 (s, 3H), 2.18 (s,3H), 1.16 (t, J=8 Hz, 3H); MS (ESI) m/z: 384.0 [M+H]⁺.

Diphosgene (2.4 mL, 19 mmol),5-((2-chloro-4-fluoro-5-nitrophenylamino)methyl)-N4-ethyl-N2-methoxy-N2-methylpyridine-2,4-diamine(6 g, 16 mmol) and Et₃N (4.6 mL, 32 mmol) were combined by the procedureof Example A4 step 3 to provide1-ethyl-3-(4-fluoro-2-methyl-5-nitro-phenyl)-7-(methoxy(methyl)amino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(4.5 g, 70% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.27 (d, J=8 Hz, 1H),7.94 (s, 1H), 7.58 (d, J=12 Hz, 1H), 6.58 (s, 1H), 4.89 (d, J=16 Hz,1H), 4.48 (d, J=16 Hz, 1H), 3.84-3.92 (m, 2H), 3.73 (s, 3H), 3.16 (s,3H), 2.20 (s, 1H), 1.19 (t, J=8 Hz, 3H); MS (ESI) m/z: 390.2 [M+H]⁺.

1-Ethyl-3-(4-fluoro-2-methyl-5-nitrophenyl)-7-(methoxy(methyl)amino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(3.2 g, 8.2 mmol) and Pd/C (0.3 g) were combined in MeOH (60 ml) andsubjected to hydrogen (45 psi) at 50° C. overnight. The reaction mixturewas filtered, concentrated in vacuo and purified by columnchromatography to give3-(5-amino-4-fluoro-2-methylphenyl)-1-ethyl-7-(methylamino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(2.1 g, 78% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 7.71 (s, 1H), 6.88 (d,J=12.0 Hz, 1H), 6.64 (d, J=8.4 Hz, 1H), 6.38 (m, 1H), 5.99 (s, 1H), 5.01(s, 2H), 4.51 (d, J=13.6 Hz, 1H), 4.29 (d, J=13.6 Hz, 1H), 3.76 (m, 2H),2.75 (d, J=4.8 Hz, 3H), 1.91 (s, 3H), 1.14 (t, J=7.2 Hz, 3H); MS (ESI)m/z: 330.2 [M+H]⁺.

Example A20

A mixture of5-(chloromethyl)-N4-ethyl-N2-methoxy-N2-methylpyridine-2,4-diamine fromExample A19 (3.2 g, 14.7 mmol) and Example D2 (2.6 g, 14.7 mol) werecombined using the procedure of Example A8 steps 2-4 to provide3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(methylamino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(2 g). ¹H NMR (400 MHz, DMSO-d₆): δ 7.72 (s, 1H), 7.24 (d, J=10.8 Hz,1H), 6.81 (d, J=9.2 Hz, 1H), 6.44 (bs, 1H), 6.02 (s, 1H), 5.42 (s, 2H),4.50 (d, J=13.2 Hz, 1H), 4.38 (d, J=13.2 Hz, 1H), 3.77 (m, 2H), 2.76 (d,J=4.8 Hz, 3H), 1.15 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 350.2[M+H]⁺.

Example A21

Example A10 (0.500 g, 1.50 mmol), mCPBA (70% 0.444 g, 1.80 mmol), andmethylamine (2 M in THF, 3.75 mL) were combined by the procedure ofExample A2 to provide3-(5-amino-4-fluoro-2-methylphenyl)-1-methyl-7-(methylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(0.363 g, 77% yield). ¹H NMR (400 MHz, DMSO-d₆), δ 7.92 (s, 1H), 7.00(s, 1H), 6.90 (d, J=11.2 Hz, 1H), 6.64 (d, J=8.4 Hz, 1H), 5.03 (s, 2H),4.48 (d, J=13.2 Hz, 1H), 4.30 (d, J=13.2 Hz, 1H), 3.22 (s, 3H), 2.78 (s,3H), 1.94 (s, 3H); MS (ESI) m/z: 317.3 [M+H⁺].

Example A22

Using a procedure analogous to Example A2, Example A9 (0.85 g, 2.447mmol), mCPBA (0.464 g, 2.69 mmol) and 2M methylamine in THF (6 mL) werecombined and purified by silica gel chromatography to afford3-(3-amino-4-fluorophenyl)-1-isopropyl-7-(methylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-oneas white solid (0.56 g, 69% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 7.93(s, 1H), 6.96 (dd, J=11.6 Hz, 8.8 Hz, 1H), 6.68 (dd, J=8.0 Hz, 2.4 Hz,1H), 6.44-6.40 (m, 1H), 5.12 (s, 2H), 4.99-4.92 (m, 1H), 4.44 (s, 2H),2.77 (d, J=4.8 Hz, 3H), 1.45 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 331:2(M+H⁺).

Example A23

Using a procedure analogous to example A2, Example A11 (0.50 g, 1.38mmol), mCPBA (0.41 g, 1.66 mmol) and methyl amine (2 M in THF, 2.8 mL,5.6 mmol) were combined to provide3-(5-amino-4-fluoro-2-methylphenyl)-1-isopropyl-7-(methylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(240 mg, 50% yield). MS (ESI) m/z: 345.0 (M+H⁺).

Example A24

To a 0° C. solution of ethyl 6-chloro-4-(methylamino)nicotinate (4 g,18.7 mmol, from Example C3) in THF (40 mL) was added LiAlH₄ (1.4 g, 37.4mmol) portionwise under a N₂ atmosphere. After stirring for 20 min, thereaction was quenched by cautious addition of water followed by aqueoussolution of 2 N NaOH. The suspension was filtered and the filtrate wasconcentrated to afford (6-chloro-4-(methylamino)pyridin-3-yl)methanol(2.9 g, 90.6% yield), which was used in next step without purification.¹HNMR (400 MHz, DMSO-d₆): δ 7.96 (s, 1H), 6.63 (s, 1H), 6.46 (s, 1H),5.04 (s, 1H), 4.39 (m, 2H), 2.81-2.68 (m, 3H).

A mixture of (6-chloro-4-(methylamino)pyridin-3-yl)methanol (2.9 g, 16.7mmol) and MnO₂ (11.7 g, 133.6 mmol) in anhydrous DCM (25 mL) was stirredat 30° C. for 6 h. The reaction mixture was cooled to RT, filtered andconcentrated in vacuo to give 6-chloro-4-(methylamino)nicotinaldehyde(2.5 g, 87% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.83 (s, 1 H), 8.52 (brs, 1H), 8.40 (s, 1H), 6.75 (s, 1H), 2.87 (d, J=5.8 Hz, 3H); MS (ESI)m/z: 171.0 [M+H]⁺.

To a solution of 6-chloro-4-(methylamino)nicotinaldehyde (1.00 g, 5.88mmol) and Example D1 (1.00 g, 5.88 mmol) in glacial acetic acid (7.5 mL)was added sodium triacetoxy borohydride (2.49 g, 11.7 mmol). The mixturewas stirred overnight at RT. Another portion of sodium triacetoxyborohydride (1.30 g, 6.11 mmol) was added and the mixture was stirredanother 24 h. The reaction was diluted with ice water and basified (pH˜7-8) with NaOH. The yellow precipitate was collected by filtration,washed with H₂O and dried under vacuum to give crude2-chloro-5-((4-fluoro-2-methyl-5-nitrophenylamino)methyl)-N-methylpyridin-4-amine(2.04 g, 107% yield), which was used without further purification. MS(ESI) m/z: 325.0 [M+H]⁺.

To suspension2-chloro-5-((4-fluoro-2-methyl-5-nitrophenylamino)methyl)-N-methylpyridin-4-amine(2.04 g, 6.28 mmol) in dioxane (30 mL) was added Et₃N (3.50 mL, 25 mmol)and phosgene (20% solution in toluene, 6.90 mL, 12.6 mmol). The reactionmixture was stirred at RT for 2.5 h. Water 30 mL) was added and themixture was extracted with EtOAc (2×70 mL). The combined organics werewashed with brine (15 mL), dried (MgSO₄) and concentrated in vacuo. Theresidue was stirred with EtOAC for 15 min and the precipitate wascollected by filtration and dried in vacuo to give7-chloro-3-(4-fluoro-2-methyl-5-nitrophenyl)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(0.785 g, 36% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.31 (s, 1H), 8.11(s, 1H), 7.61 (s, 1H), 7.15 (s, 1H), 4.94 (s, 1H), 4.61 (s, 1H), 3.26(s, 3H), 2.22 (s, 3H); MS (ESI) m/z: 351.0 [M+H⁺].

Zn Dust (0.575 g, 8.80 mmol) was added to a suspension of7-chloro-3-(4-fluoro-2-methyl-5-nitrophenyl)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(0.309 g, 0.880 mmol) and NH₄Cl (0.471 g, 8.80 mmol in MeOH/THF (1:1, 16mL) and the mixture was stirred 1.5 h at RT. The mixture was filteredthrough Celite, rinsing forward with MeOH and the filtrates wereconcentrated, diluted with brine and extracted with THF (2×). Thecombined organics layers were washed with brine, dried (MgSO4), andconcentrated to afford3-(5-amino-4-fluoro-2-methylphenyl)-7-chloro-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(0.260 g, 92% yield). MS (ESI) m/z: 321.0 [M+H⁺].

Example A25

Example A24 (0.260 g, 0.811 mmol) and N′,N′-dimethylethane-1,2-diamine(9.25 mL) were combined and heated to 175° C. for 2 days. The excesssolvent was removed under reduced pressure. And the residue waspartitioned with saturated aq NaHCO₃ (15 mL) and EtOAc (2×35 mL). Thecombined organics were washed with brine (15 mL), dried (MgSO4) andconcentrated. The light yellow residue was dissolved in minimal amountof EtOAc. Hexane was added and the mixture was stirred for 15 min. Theprecipitate was collected by filtration, washed with hexane and driedunder vacuum to obtain3-(5-amino-4-fluoro-2-methylphenyl)-7-(2-(dimethylamino)ethylamino)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(0.153 g, 51% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 7.68 (s, 1H), 6.88(d, J=12.0 Hz, 1H), 6.62 (d, J=8.8 Hz, 1H), 6.25 (t, J=5.4 Hz, 1H), 6.03(s, 1H), 5.00 (s, 2H), 4.49 (d, J=13.6 Hz, 1H), 4.30 (d, J=13.6 Hz, 1H),3.29 (m, 2H), 3.13 (s, 3H), 2.38 (t, J=6.4 Hz, 2H), 2.16 (s, 6H), 1.91(s, 3H).

Example A26

5-(Chloromethyl)-N4-ethyl-N2-methoxy-N2-methylpyridine-2,4-diamine (4.3g, 18.7 mmol, from Example A19) and 4-fluoro-3-nitro-phenylamine (3 g,19 mmol) were combined in pyridine (50 mL) by the method of Example A4to provideN4-ethyl-5-((4-fluoro-3-nitrophenylamino)methyl)-N2-methoxy-N2-methylpyridine-2,4-diamine(5.6 g, 85% yield). ¹H NMR (400 MHz, DMSO-d₆): A 7.65 (s, 1H), 7.63 (s,1H), 7.34-7.29 (m, 1H), 7.23-7.21 (m, 1H), 7.02-7.6.98 (m, 1H), 6.84 (s,1H), 6.06 (s, 1H), 4.18 (d, J=3.2 Hz, 2H), 3.71 (s, 3H), 3.31 (s, 3H),3.32 (q, J=7.2 Hz, 2H), 1.18 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 350.1[M+H]⁺.

Diphosgene (2.4 mL, 20 mmol),N4-ethyl-5-((4-fluoro-3-nitrophenylamino)methyl)-N2-methoxy-N2-methylpyridine-2,4-diamine(5.6 g, 16 mmol) and Et₃N (4.3 g, 40 mmol) were combined by theprocedure of Example A4 to provide1-ethyl-3-(4-fluoro-3-nitrophenyl)-7-(methoxy(methyl)amino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(4.8 g, 80% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.14 (m, 1H), 7.96 (s,1H), 7.79 (m, 1H), 7.61 (m, 1H), 6.57 (s, 1H), 4.78 (s, 2H), 3.88 (d,J=7.2 Hz, 2H), 3.71 (s, 3H), 3.15 (s, 3H), 1.20 (t, J=7.2 Hz, 3H); MS(ESI) m/z: 376.2 [M+H]⁺.

1-Ethyl-3-(4-fluoro-3-nitrophenyl)-7-(methoxy(methyl)amino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(4.6 g, 12 mmol), Pd/C (0.5 g) and hydrogen (45 psi) were reacted inMeOH (100 mL) at 50° C. overnight to give3-(3-amino-4-fluorophenyl)-1-ethyl-7-(methylamino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(3.2 g, 84%). ¹H-NMR (400 MHz, DMSO-d₆): A 7.70 (s, 1H), 6.94 (dd,J=11.2, 8.8 Hz, 1H), 6.67 (dd, J=8.0, 2.4 Hz, 1H), 6.42 (m, 1H), 6.33(m, 1H), 5.98 (s, 1H), 5.14 (s, 2H), 4.48 (s, 2H), 3.74 (q, J=7.2 Hz,2H), 2.73 (d, J=5.2 Hz, 3H), 1.15 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 316.2[M+H]⁺.

Example A27

To a solution of Example A10 (0.500 g, 1.50 mmol) in CH₂Cl₂ (10 mL) wasadded mCPBA (0.444 g, 1.20 eq) in a portion wise manner. After stirringfor 1 h, N′,N′-dimethylethane-1,2-diamine (0.661 g, 7.5 mmol) was addedand the reaction mixture was stirred overnight. Water was added and thesolution was stirred for 1 h. The aqueous was extracted with CH₂Cl₂ (2×)and the combined organics were washed with saturated NaHCO₃, 3N NaOH,and brine. The organics were dried (MgSO₄) and concentrated to provide3-(5-amino-4-fluoro-2-methylphenyl)-7-(2-(dimethylamino)ethylamino)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(0.358 g, 64%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.91 (s, 1H), 6.92-6.88 (m,2H), 6.64 (d, J=8.8 Hz, 1H), 5.03 (s, 2H), 4.48 (d, J=14.0 Hz, 1H), 4.30(d, J=14.0 Hz, 1H), 4.33 (m, 2H), 3.22 (s, 3H), 2.38 (t, J=6.8 Hz, 2H),2.16 (s, 6H), 1.94 (s, 3H).

Example A28

Using a procedure analogous to Example A17,5-(chloromethyl)-N4-isopropyl-N2-methoxy-N2-methylpyridine-2,4-diamine(3.3 g, 13.6 mmol, see Example A17) and 4-fluoro-5-nitroaniline (2.1 g,13.6 mol) were combined to provide3-(3-amino-4-fluorophenyl)-1-isopropyl-7-(methylamino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(2.1 g, 47% yield over 3 steps). ¹H NMR (400 MHz, DMSO-d₆): δ 7.81 (s,1H), 7.02 (dd, J=11.2, 8.8 Hz, 1H), 6.74 (dd, J=8.0, 2.4 Hz, 1H),6.48-6.43 (m, 2H), 6.22 (s, 1H), 5.24 (s, 2H), 4.49 (s, 2H), 4.39 (m,1H), 2.82 (d, J=4.8 Hz, 3H), 1.52 (d, J=6.8 Hz, 6H); MS (ESI) m/z:330.2. [M+H]⁺.

Example A29

A solution of ethyl 4,6-dichloronicotinate (10 g, 45.7 mmol) intert-butylamine (100 mL) was stirred at 50° C. for 10 h. The solvent wasremoved under reduced pressure and the residue was suspended in H₂O andextracted with EtOAc (3×100 mL). The organics were washed with brine,dried (MgSO₄), concentrated in vacuo and purified by silica gelchromatography to provide ethyl 4-(tert-butylamino)-6-chloronicotinate(7 g, 60% yield). ¹HNMR (400 MHz, DMSO-d₆): δ 8.53 (s, 1H), 8.39 (s,1H), 6.80 (s, 1H), 4.25 (d, J=7.2 Hz, 2 H), 1.37 (s, 9H), 1.27 (t, J=7.2Hz, 3H).

LiAlH₄ ((2.1 g, 54.7 mmol) was added portion wise to a 0° C. solution ofethyl 4-(tert-butylamino)-6-chloronicotinate (7 g, 27.3 mmol) in THF(100 mL). After 20 min, the reaction was quenched by the addition ofwater (2.1 mL), followed by 2 N aq NaOH (2 N, 2.1 ml. The resultingsuspension was filtered and the filtrate was concentrated to afford(4-tert-butylamino-6-chloro-pyridin-3-yl)-methanol (5.0 g, 86.2% yield),which was used in next step without purification. ¹H NMR (400 MHz,DMSO-d₆): δ 7.73 (s, 1H), 6.61 (s, 1H), 5.87 (s, 1H), 5.43 (t, J=5.2 Hz,1H), 4.38 (d, J=5.2 Hz, 2H), 1.35 (s, 9H).

A mixture of (4-tert-butylamino-6-chloro-pyridin-3-yl)-methanol (5.0 g,23.4 mmol) and MnO₂ (14.3 g, 163.6 mmol) in anhydrous CH₂Cl₂ (100 mL)was stirred at RT for 10 h. The reaction was filtered and the filtratewas concentrated to give 4-(tert-butylamino)-6-chloronicotinaldehyde(4.0 g, 87.0% yield), which was used in the next step without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆): δ 9.83 (s, 1H), 8.90 (s, 1H),8.44 (s, 1H), 6.86 (s, 1H), 1.40 (s, 9H).

A mixture of 4-(tert-butylamino)-6-chloronicotinaldehyde (4.0 g, 18.9mmol), 4-fluoro-3-nitroaniline (2.9 g, 18.9 mmol) and NaBH(OAc)₃ (7.1 g,37.8 nmol) in CH₃COOH (80 mL) was heated to 80° C. for 10 h. Thereaction was concentrated under reduced pressure to give a sticky solid,which was suspended in ice water. The mixture was neutralized (pH 7)with 2N aqueous NaOH solution and was extracted with EtOAc. The extractswere washed with brine, dried (Na₂SO₄) and concentrated in vacuo.Purification of the residue by chromatography providedN-tert-butyl-2-chloro-5-((4-fluoro-3-nitrophenylamino)methyl)pyridin-4-amine(4.3 g, 65% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 7.87 (s, 1H), 7.32 (m,1H), 7.27 (m, 1H), 7.04 (m, 1H), 6.68 (s, 1H), 6.52 (m, 1H), 5.46 (s,1H), 4.17 (d, J=4.8 Hz, 2H), 1.36 (s, 9H).

NaH (1.5 g, 36.6 mmol) was added portion wise to a solution ofN-tert-butyl-2-chloro-5-((4-fluoro-3-nitrophenylamino)methyl)pyridin-4-amine(4.3 g, 12.2 mmol) in anhydrous dioxane (400 mL) at 0° C. and theresulting mixture was stirred at RT for 10 min. A solution oftriphosgene (3.6 g, 12.2 mmol) in dioxane (30 mL) was added to the abovemixture at 0° C. After the addition, the mixture was heated at 100° C.for 10 h. The cooled reaction was quenched with water and the pH wasadjusted to pH>7 with saturated NaHCO₃ solution. The dioxane was removedunder reduced pressure and the residue was partitioned between water andEtOAc (3×50 mL). The combined organic layers were washed with brine,dried (Na₂SO₄) and concentrated in vacuo. Purification by silica gelchromatography provided1-tert-butyl-7-chloro-3-(4-fluoro-3-nitrophenyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(3.5 g, 76% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.21 (s, 1H), 8.07 (m,1H), 7.71 (m, 1H), 7.57 (m, 1H), 7.32 (s, 1H), 4.70 (s, 2H), 1.57 (s,9H).

Iron powder was added (5.2 g, 93 mmol) in portions to a solution of1-tert-butyl-7-chloro-3-(4-fluoro-3-nitrophenyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(3.5 g, 9.3 mmol) and cone. HCl (0.35 mL, 4.2 mmol) in 10/1 EtOl/H₂O (11mL). The resulting mixture was stirred at 40° C. for 30 min. Thereaction mixture was filtered and the filter cake was washed with EtOH.The ethanolic filtrate was concentrated and the residue was partitionedbetween EtOAc and H₂O. The aqueous layer was extracted with EtOAc (3×80mL). The combined organics were washed with brine, dried (Na₂SO₄),concentrated in vacuo and purified by chromatography on silica gel toafford3-(3-amino-4-fluorophenyl)-1-tert-butyl-7-chloro-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(2.0 g, 62% yield). ¹HNMR (400 MHz, DMSO-d₆): δ 8.20 (s, 1H), 7.26 (s,1H), 6.92 (m, 1H), 6.62 (m, 1H), 6.34 (m, 1H), 5.17 (s, 2H), 4.50 (s, 2H), 1.55 (s, 9H).

3-(3-Amino-4-fluorophenyl)-1-tert-butyl-7-chloro-3,4-dihydro-1H-pyrido[4,3-d]pyrimidin-2-one(2.0 g, 5.7 mmol), CuI (200 mg, 1.05 mmol) and methylamine (200 mL) werecombined in a steel bomb and heated to 180° C. for 48 h. The reactionvessel was cooled to −78° C., unsealed, and warmed to RT. The reactionwas partitioned between EtOAc and H₂O, and the aqueous layer wasextracted with EtOAc. The combined organics were washed with brine(2×100 mL), dried (Na₂SO₄), concentrated and purified by neutralaluminum oxide column chromatography to provide3-(3-amino-4-fluorophenyl)-1-tert-butyl-7-(methylamino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(900 mg, 46% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 7.76 (s, 1H), 6.91(dd, J=11.1, 8.7 Hz, 1H), 6.61 (dd, J=8.1, 2.4 Hz, 1H), 6.35-6.32 (m,3H), 5.14 (s, 2H), 4.29 (s, 2H), 2.74 (d, J=4.8 Hz, 3H), 1.55 (s, 9H);MS (ESI) m/z: 344.0 [M+H]⁺.

Example A30

By analogy to Example A24, 6-chloro-4-(methylamino)nicotinaldehyde (fromExample A24), 4-fluoro-3-nitroaniline and sodium triacetoxy borohydrideare combined in glacial acetic acid to give crude2-chloro-5-((4-fluoro-3-nitrophenylamino)methyl)-N-methylpyridin-4-amine,which is reacted with diphosgene by the procedure of Example A75 to give7-chloro-3-(4-fluoro-3-nitrophenyl)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one.Zn Dust is reacted with a suspension of7-chloro-3-(4-fluoro-3-nitrophenyl)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-oneand NH₄Cl in MeOH/THF (1:1) to provide3-(3-amino-4-fluorophenyl)-7-chloro-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one.By analogy to Example A25, 4-methoxybenzylamine and3-(3-amino-4-fluorophenyl)-7-chloro-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-oneare combined and heated to 180° C. to provide7-(4-methoxybenzylamino)-3-(3-amino-4-fluorophenyl)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one,which is further reacted with trifluoroacetic acid to provide7-amino-3-(3-amino-4-fluorophenyl)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one.

Example A31

S2-Amino-6-(5-amino-4-fluoro-2-methylphenyl)-8-methylpteridin-7(8H)-onecan be prepared by the procedure of Example A5 by substitutingN4-methylpyrimidine-2,4,5-triamine sulfate (O'Brien, et. al. J. Med.Chem. (1966), 9, p 121-6) for Example D3.

Example A32

A mixture of5-(chloromethyl)-N4-ethyl-N2-methoxy-N2-methylpyridine-2,4-diamine (3.2g, 14.7 mmol, from Example A9) and Example D2 (2.6 g, 14.7 mol) werecombined using the procedure of Example A4 to provide5-((2-chloro-4-fluoro-5-nitrophenylamino)methyl)-N4-ethyl-N2-methoxy-N2-methylpyridine-2,4-diamine(4.3 g, 76% yield), which was used in the next step without furtherpurification.

Diphosgene (3.1 g, 15.66 mmol),5-((2-chloro-4-fluoro-5-nitrophenylamino)methyl)-N4-ethyl-N2-methoxy-N2-methylpyridine-2,4-diamine(4.3 g, 13.1 mmol) and Et₃N (7 g, 65.2 mmol) were combined by theprocedure of Example A4 to give3-(2-chloro-4-fluoro-5-nitrophenyl)-1-ethyl-7-(methoxy(methyl)amino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(2.7 g, 60% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.55 (d, J=7.6 Hz, 1H),8.09 (d, J=11.2 Hz, 1H), 8.00 (s, 1H), 6.63 (s, 1H), 4.91 (d, J=13.6 Hz,1H), 4.55 (d, J=13.6 Hz, 1H), 3.93 (m, 2H), 3.77 (s, 3H), 3.20 (s, 3H),1.23 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 410.2[M+H]⁺.

3-(2-Chloro-4-fluoro-5-nitrophenyl)-1-ethyl-7-(methoxy(methyl)amino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(2.7 g, 6.6 mmol), Pd/C (1.4 g) and hydrogen (30 psi) were combined at45° C. by the procedure of Example A4 to provide3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(methylamino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(2 g, 87.0% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 7.72 (s, 1H), 7.24 (d,J=10.8 Hz, 1H), 6.81 (d, J=9.2 Hz, 1H), 6.44 (bs, 1H), 6.02 (s, 1H),5.42 (s, 2H), 4.50 (d, J=13.2 Hz, 1H), 4.38 (d, J=13.2 Hz, 1H), 3.77 (m,2H), 2.76 (d, J=4.8 Hz, 3H), 1.15 (t, J=7.2 Hz, 3H); MS (ESI) m/z:350.2[M+H]⁺.

Example B1

Phenyl hydrazine and 4,4-dimethyl-3-oxopentanenitrile were combinedaccording to literature procedures to yield3-tert-butyl-1-phenyl-1H-pyrazol-5-amine. See WO 2006/071940.

Example B2

To a solution of quinolin-6-ylamine (5 g, 35 mmol) in conc. HCl (12 mL)was added dropwise an aqueous solution (4 mL) of NaNO₂ (2.42 g, 35 mmol)at 0° C. The resulting mixture was stirred for 1 h and then treateddropwise with a solution of SCl₂.2H₂O (15.8 g, 70 mmol) in conc. HCl (15mL) at 0° C. The reaction mixture was stirred for 2 h at RT. Theprecipitate was collected and washed with EtOH and Et₂O to yield1-(quinolin-6-yl)hydrazine hydrochloride (4.3 g, 77% yield) as a yellowpowder, which was used for the next reaction without furtherpurification.

A mixture of 1-(quinolin-6-yl)hydrazine hydrochloride (4.0 g, 20.5 mmol)and 4,4-dimethyl-3-oxo-pentanenitrile (3.6 g, 30 mol) in EtOH (50 mL)and conc. HCl (5 mL) was heated at reflux overnight. After removal ofthe solvent, the residue was purified by column chromatography to yield3-t-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-amine (2.8 g, 51% yield). ¹HNMR (300 MHz, DMSO-d₆): δ 8.84 (d, J=4.2 Hz, 1H), 8.37 (d, J=7.5 Hz,1H), 8.09 (s, 1H), 8.04 (s, 2H), 7.52 (m, 1H), 5.46 (s, 1H), 5.40 (brs,2H), 1.29 (s, 9H).

Example B3

3-t-butylisoxazol-5-amine was prepared according to the method disclosedin WO 99/32111, 0.250.

Example B4

4,4,4-Trifluoro-3-oxo-butyronitrile and phenylhydrazine were combined bythe procedure of Example B11 to provide1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-amine. 1H-NMR (400 MHz,DMSO-d₆) δ 7.59-7.50 (m, 4H), 7.42 (m, 1H), 5.78 (s, 1H), 5.73 (br s,2H).

Example B5

ethyl hydrazine and 4,4-dimethyl-3-oxopentanenitrile were combinedaccording to literature procedures to yield3-tert-butyl-1-methyl-1H-pyrazol-5-amine. See WO 2006/071940.

Example B6

A mixture of 1,1,3,3-tetramethoxypropane (37 g, 226 mmol),tert-butyl-hydrazine hydrochloride (28 g, 226 mmol) and cone HCl (60 mL,720 mmol) in EtOH (300 mL) was heated at reflux overnight. The mixturewas poured into water and the resulting mixture was extracted withether. The combined organics were washed with brine, dried (MgSO₄) andconcentrated in vacuo to give 1-tert-butyl-1H-pyrazole (25 g, 89%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 7.73 (s, 1H), 7.38 (s, 1H), 6.17(s, 1H), 1.47 (s, 9H); MS (ESI) m/z: 125.1 [M+H]⁺.

HNO₃ (11.7 g, 185 mmol) was added dropwise to a mixture of1-tert-butyl-1H-pyrazole (23 g, 185 mmol) in conc. H₂SO₄ (30 mL) at 0°C. The resulting mixture was stirred at 0° C. for min and was pouredonto crashed ice. The aqueous mixture was extracted with EtOAc. Thecombined organics were washed with brine, dried (MgSO₄) and concentratedin vacuo to give 1-tert-butyl-4-nitro-1H-pyrazole (20 g, 64% yield). ¹HNMR (400 MHz, DMSO-d₆): δ 8.85 (s, 1 H), 8.23 (s, 1H), 1.52 (s, 9H).

Example B7

To a suspension of Na₂CO₃ (36 g, 339 mmol) in CH₂Cl₂ (300 mL) was added1-t-butyl-1H-pyrazole from Example B19 (21 g, 170 mmol) and Br₂ (9 mL),and the resulting mixture was stirred at RT overnight. The solid wasremoved by filtration and the filter cake was washed with CH₂Cl₂. Thefiltrates were washed with water and brine, dried (MgSO₄), andconcentrated to give crude 4-bromo-1-t-butyl-1H-pyrazole (29 g, 85%),used without further purification. ¹H NMR (300 MHz, CDCl₃): δ 7.49 (s,1H), 7.45 (s, 1H), 1.53 (s, 9H); MS (ESI) m/z: 203 [M+H]⁺.

To a −78° C. solution of 4-bromo-1-t-butyl-1H-pyrazole (15 g, 74.3 mmol)in anhydrous THF (100 mL) was added n-BuLi (2.5 M in hexane, 53 mL, 132mmol) under N₂, and the resulting mixture was stirred at −78° C. for 30min. Excess dry ice was added at −78° C., and the mixture was warmedslowly to RT and stirred overnight. The reaction was concentrated invacuo, water was added and the pH was adjusted to pH 3 by the additionof 2N aq HCl. The aqueous solution was extracted with EtOAc. Theextracts were washed with brine, dried (MgSO₄) and concentrated invacuo. The residue was recrystallized (EtOAc-pet. ether) to give1-t-butyl-1H-pyrazole-4-carboxylic acid (8.0 g, 67% yield). ¹H NMR (300MHz, CDCl₃): δ 8.10 (s, 1H), 8.03 (s, 1H), 1.64 (s, 9H); MS (ESI) m/z:168.9 [M+H]⁺.

Example B8

In ethanol (10 mL) was placed the tert-butylhydrazine hydrochloride(1.35 g, 10.8 mmol) and ethyl2-((dimethylamino)methylene)-3-oxobutanoate (2.00 g, 10.8 mmol). Themixture warmed to reflux and stirred for 2 hrs, cooled to RT and stirredovernight. The mixture was evaporated at reduced pressure to give an oilwhich was dissolved in ether (25 mL) and washed successively with water(25 mL), saturated sodium bicarbonate (25 mL) and brine (25 mL), dried(Na₂SO₄) and evaporated at reduced pressure to give an oil. The oil waspurified by chromatography (Biotage S1-25 column, 10-40% ethylacetate/Hex—750 mL) to give ethyl1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylate (1.48 g, 65% yield) asan oil. MS (ESI) m/z: 211.0 (M+H⁺).

In a mixture of ethanol:water:dioxane (1:1:1, 21 mL) was placed ethyl1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylate (1.48 g, 7.04 mmol) andlithium hydroxide hydrate (886 mg, 21.12 mmol). The reaction was stirredat 40 C for 3 hrs and then at RT overnight. The reaction was dilutedwith water (25 mL) and ether (25 mL). The ether layer was discarded andthe aqueous phase made acidic (pH˜=4) with 1N HCl. The acidic phase wasthen extracted with ethyl acetate (2×25 mL) and the combined ethylacetate layers were washed with brine, dried (Na₂SO₄), evaporated atreduced pressure to give 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylicacid as a white solid (1.12 g, 87% yield). ¹H NMR (300 MHz, DMSO-d₆): δ1.56 (s, 9H), 2.67 (s, 3H), 7.65 (s, 1H), 12.13 (s, 1H); MS (ESI) m/z:183.0 (M+H⁺).

Example B9

To a suspension of KCN (1.90 g, 29.1 mmol) in MeOH (35 mL) was addeddropwisely 3-bromo-1,1,1-trifluoropropan-2-one oxime (5.00 g, 24.3 mmol)in MeOH (72 mL) at RT. The reaction mixture was stirred at RT for 3hours. The solution was evaporated and then the residue was dissolved inEtOAc and stirred at RT. The solid was filtered (KBr) and the filtratewas evaporated to obtain the crude product. The crude product waspurified by silica gel column chromatography (Biotage: 25M, 10% to 60%EtOAc/hexane: 550 mL). Pure fractions were combined and evaporated toobtain 3-(trifluoromethyl)isoxazol-5-amine (1.38 g, 37% yield). MS (ESI)m/z: 153.0 (M+H⁺).

Example B10

In ethanol (40 mL) was placed t-butylcarbamidine hydrochloride (3.71 g,27.2 mmol). This was treated with 21% sodium ethoxide in ethanol (8.80g, 27.2 mmol) and stirred at RT for 15 min. To this was added thediethyl ethoxymethylenemalonate (5.87 g, 27.2 mmol) and the reactionmixture was stirred overnight at RT. The reaction mixture was refluxedfor 1 hour and then cooled to RT. The solution was evaporated and theresidue was dissolved in water (100 mL) and the pH adjusted to 3-4 (wetlitmus) with acetic acid. The mixture formed a precipitate. The solidcollected by filtration, washed with water (50 mL) and dried undervacuum to obtain ethyl 2-tert-butyl-4-hydroxypyrimidine-5-carboxylate(2.18 g, 36% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 12.6 (brs, 1H), 8.44(s, 1H), 4.20 (q, J=7.2 Hz, 2H), 1.25 (s, 9H), 1.23 (t, J=7.2 Hz, 3H);MS (ESI) m/z: 225.0 (M+H⁺).

In cold (˜0° C.) POCl₃ (20 mL) was dropped triethylamine (0.55 mL) withstirring. To this was added in parts of ethyl2-tert-butyl-4-hydroxypyrimidine-5-carboxylate (2.18 g, 9.72 mmol). Themixture then warmed to 40° C. and stirred under Argon for 1 hour. Themixture was evaporated until free of POCl₃, diluted with CHCl₃ (100 mL)and poured carefully into ice (300 mL). The solution was stirred at RTto melt. The organic phase was separated, washed with sodium bicarbonate(100 mL), water (100 mL) and dried (Na₂SO₄). The solvents evaporated togive ethyl 2-tert-butyl-4-chloropyrimidine-5-carboxylate (2.0 g, 85%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.12 (s, 1H), 4.34 (q, J=6.8 Hz,2H), 1.33 (s, 9H), 1.27 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 243.0 (M+H⁺).

To a stirring suspension of ethyl4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-tert-butylpyrimidine-5-carboxylate(0.49 g, 1.24 mmol) in 1:1:1 THF/EtOH/H₂O (9 ml) at RT was addedLiOH.H₂O (120 mg, 4.94 mmol) and the mixture was stirred overnight atRT. The reaction mixture was checked by LC-MS and the completed reactionwas concentrated to an aqueous residue, acidified (pH 3-4) with 3M HCland the solution was extracted with EtOAc (3×). The combined organicswere washed with brine (1×), dried (MgSO4), filtered and concentration.The crude was dissolved in isopropanol and the solid (LiCl and NaCl) wasfiltered and washed with isopropanol. The filtrate was concentrated toobtain the desired product4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-tert-butylpyrimidine-5-carboxylicacid (0.36 g, 80% yield). MS (ESI) m/z: 365.0 (M+H⁺).

Example B11

A solution of ethyl trifluoroacetate (14.2 g, 0.1 mol) and anhydrousacetonitrile (5.0 g, 0.12 mol) in THF (100 mL) was added dropwise to asuspension of NaH (60%, 6.0 g, 0.15 mol) in THF (100 mL) at 80° C. Theresulting mixture was heated to reflux overnight, and then cooled to RT.The reaction mixture was concentrated in vacuo and the residue wasdiluted with EtOAc and 10% aq HCl. The organic layer was washed withwater and brine, dried (MgSO₄) and concentrated in vacuo to yield crude4,4,4-trifluoro-3-oxo-butyronitrile (15 g), which was used withoutfurther purification.

A solution of methylhydrazine (5.0 g, 60 mmol) and4,4,4-trifluoro-3-oxo-butyronitrile (9.8 g, 71 mmol) in EtOH (50 mL) wastreated with cone. HCl (5 mL) and the resultant mixture was heated toreflux overnight. The solvent was removed in vacuo and the crude productwas dissolved in EtOAc washed with saturated aq. Na₂CO₃ solution untilthe washings were pH 8. The organics were concentrated and purified bypre-HPLC to provide 2-methyl-5-trifluoromethyl-2H-pyrazol-3-ylamine(2.07 g, 21% yield). ¹HNMR (300 MHz, DMSO-d6), δ 5.57 (s, 1H), 5.54 (brs, 2H), 3.55 (s, 3H); MS (ESI) m/z: 166.1 (M+H⁺).

Example B12

To a stirring solution of ethyl2-(5-amino-1-phenyl-1H-pyrazol-3-yl)-2-methylpropanoate (DP-2440, 0.240g, 0.86 mmol) in dry THF (8.0 mL) at RT was added LiAlH₄ (1.0 M in THF,2.6 mL, 2.6 mmol) and the resulting mixture was stirred at RT for 1 h.The reaction was carefully quenched by the addition of H₂O (0.10 mL), 3MNaOH (0.10 mL) and H₂O (0.20 mL), and the mixture was stirred at RTovernight. The suspension was filtered through Celite and rinsed withEtOAc (20 mL). The filtrate was dried (MgSO₄) and concentrated to afford2-(5-amino-1-phenyl-1H-pyrazol-3-yl)-2-methylpropan-1-ol (0.208, 105%yield) as a yellow oil. MS (ESI) m/z: 232.2 (M+H⁺).

To a solution of above2-(5-amino-1-phenyl-1H-pyrazol-3-yl)-2-methylpropan-1-ol (0.208 g, 0.85mmol) in DMF (2.0 mL) was added imidazole (0.32 g, 4.7 mmol) and TBSCl(0.39 g, 2.6 mmol). The resulting mixture was stirred at RT for 5 h.Solvent was removed under reduced pressure. The residue was diluted withH₂O (10 mL) and extracted with EtOAc (2×20 mL). The combined organiclayers were dried (MgSO₄) and concentrated. The crude product waspurified by chromatography to afford3-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-amine(0.125 g, 42% yield) as a light yellow oil. MS (ESI) m/z: 346.3 (M+H⁺).

Example B13

Using a procedure analogous to Example B13, ethyl2-(5-amino-1-methyl-1H-pyrazol-3-yl)-2-methylpropanoate (DP-2525) wasconverted to3-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-1-methyl-1H-pyrazol-5-aminein 42% yield. ¹H NMR (400 MHz, CDCl₃): δ 5.59 (s, 1H), 3.69 (s, 3H),3.55 (s, 2H), 1.26 (s, 6H), 0.89 (s, 9H), 0.00 (s, 6H); MS (ESI) m/z:284.2 (M+H⁺).

Example C1

A solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (42g, 181 mmol) in EtOH (400 mL) was treated with a solution of methylamine(12.3 g, 397 mmol) in EtOH (100 mL) at 0° C. and the mixture was stirredfor 3 h. The mixture was concentrated and then partitioned between H₂O(200 mL) and CH₂Cl₂ (500 mL). The organic layer was washed with brine,dried (Na₂SO₄) and concentrated in vacuo to give ethyl4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate as a white solid(36.0 g, 88% yield). ¹H NMR (300 MHz, CDCl₃): 8.59 (s, 1H), 8.18 (br s,1H), 4.31 (q, J=7.2 Hz, 2H), 3.05 (d, J=4.8 Hz, 3H), 2.52 (s, 3H), 1.34(t, J=7.2 Hz, 3H); MS (ESI) m/z: 228.1 (M+H⁺).

To a solution of ethyl4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate (30 g, 132 mmol)in THF (300 mL) was added LiAlH₄ (7.5 g, 198 mmol). The reaction mixturewas stirred for 1 h at RT. The reaction was carefully quenched with 10mL water, 7 mL of 10% aq NaOH. The mixture was stirred for 1 h, filteredand the filtrate was concentrated to give(4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methanol (22.0 g, 90%yield). ¹H NMR (300 MHz, DMSO-d₆): 7.79 (s, 1H), 6.79 (m, 1H), 5.04 (t,J=5.4 Hz, 1H), 4.27 (d, J=5.4 Hz, 2 H), 2.83 (d, J=4.8 Hz, 3H), 2.40 (s,3H). MS (ESI) m/z: 186.1 (M+H⁺).

Example C2

A mixture of Example C1 (22.0 g, 119 mmol) and MnO₂ (44 g, 506 mmol) inCHCl₃ (300 mL) was stirred at RT for 3 h. The reaction was filtered andthe filtrate was concentrated to give4-(methylamino)-2-(methylthio)pyrimidine-5-carbaldehyde as a pale solid(20 g, 92% yield). ¹H NMR (400 MHz, DMSO-d₆): 9.71 (s, 1H), 8.60 (br s,1H), 8.49 (s, 1H), 2.96 (d, J=4.8 Hz, 3H), 2.48 (s, 3H) MS (ESI) m/z:184.0 (M+H⁺).

Example C3

To a solution of ethyl 4,6-dichloronicotinate (5 g, 22.8 mmol) in CH₃CN(30 mL) was added dropwise aqueous methylamine (65%, 5.2 g, 45.6 mmol)at 0° C. The resulting mixture was stirred at RT for 8 h. The organicsolution was removed under reduced pressure to give the crude product,which was suspended in H₂O and extracted with EtOAc (3×20 mL). Thecombined extracts were washed with brine, dried (MgSO₄) and concentratedto give ethyl 6-chloro-4-(methylamino)nicotinate (4 g, 82% yield), whichwas used in the next step without further purification. ¹HNMR (300 MHz,DMSO-d₆): δ 8.48 (s, 1H), 8.04 (d, J=4.5 Hz, 1H), 6.71 (s, 1H), 4.27 (q,J=6.9 Hz, 2H), 2.85 (d, J=5.1 Hz, 3H), 1.29 (t, J=6.9 Hz, 3H).

A mixture of ethyl 6-chloro-4-(methylamino)nicotinate (8 g, 37.4 mmol)and O,N-dimethylhydroxylamine hydrochloride (91 g, 0.94 mol) in dioxane(10 mL) was heated to 180° C. for 6 h. The reaction mixture was cooledto RT, and saturated aq Na₂CO₃ solution was added until pH 7. Theaqueous solution was extracted with EtOAc (3×100 mL). The combinedorganics were washed with brine, dried (MgSO₄) and concentrated in vacuoto give ethyl 6-(methoxy(methyl)amino)-4-(methylamino)nicotinate (6.6 g,74% yield), which was used in the next step without furtherpurification. ¹HNMR (400 MHz, DMSO-d₆): δ 8.44 (s, 1H), 7.82 (m, 1H),6.05 (s, 1H), 4.20 (q, J=7.2 Hz, 2H), 3.67 (s, 3H), 3.17 (s, 3H), 2.82(d, J=5.2 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H), MS (ESI) m/z: 240.1 (M+H⁺)

To a solution of ethyl6-(methoxy(methyl)amino)-4-(methylamino)nicotinate (6 g, 25 mmol) in THF(60 mL) at 0° C. was added LiAlH₄ (1.9 g, 50.2 mmol) in portions underN₂ atmosphere. After 20 min, the reaction was quenched by addition ofwater followed by aqueous 2N NaOH. The resultant suspension was filteredand the filtrate was concentrated in vacuo to afford(6-(methoxy(methyl)amino)-4-(methylamino)pyridin-3-yl)methanol (3.8 g,77.6% yield), which was used without further purification. ¹H NMR (400MHz, DMSO-d₆): δ 7.61 (s, 1H), 6.08 (s, 1H), 5.86 (m, 1H), 4.88 (t,J=5.2 Hz, 1H), 4.30 (d, J=5.2 Hz, 2H), 3.64 (s, 3H), 3.04 (s, 3H), 2.73(d, J=4.8 Hz, 3H); MS (ESI) m/z: 198.2 (M+H⁺).

Example C4

To a 0° C. solution of ethyl4-chloro-2-(methylthio)pyrimidine-5-carboxylate (19 g, 82 mmol) in CH₃CN(100 mL) was added a solution of aqueous ethylamine (70%, 8.1 g, 126mmol). The resulting mixture was stirred at RT for 8 h. The organicsolution was removed under reduced pressure, and the residue waspartitioned between EtOAc and H₂O. The aqueous layer was extracted withethyl acetate (3×30 mL) and the combined organics were washed withbrine, dried (MgSO₄) and concentrated to give ethyl4-(ethylamino)-2-(methylthio)pyrimidine-5-carboxylate (19.5 g, 99.1%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.49 (s, 1H), 8.26 (t, J=4.8 Hz,1H), 4.23 (q, J=7.2 Hz, 2H), 3.48 (q, J=7.2 Hz, 2H), 2.44 (s, 3H), 1.26(t, J=7.2 Hz, 3H), 1.13 (t, J=7.2 Hz, 3H).

To a solution of ethyl4-(ethylamino)-2-(methylthio)pyrimidine-5-carboxylate (19.5 g, 81.9mmol) in anhydrous THF (100 mL) was added LiAH₄ (12.3 g, 327.6 mmol) inportions at 0° C. under N₂ atmosphere. After stirring for 30 min, thereaction was quenched with water and then 2N aqueous NaOH as added. Thesuspension was filtered and the filtrate was concentrated to afford(4-(ethylamino)-2-(methylthio)pyrimidin-5-yl)methanol (15 g, 92.0%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 7.78 (s, 1H), 6.74 (t, J=4.8 Hz,1H), 5.05 (t, J=5.2 Hz, 1H), 4.26 (d, J=5.2 Hz, 2H), 3.36 (m, 2H), 2.37(s, 3H), 1.10 (m, 3H).

Example C5

Activated MnO₂ (52 g, 0.6 mol) was added to a solution of(4-(ethylamino)-2-(methylthio)pyrimidin-5-yl)methanol (15 g, 0.075 mol)in CH₂CL₂ (300 mL) and the reaction mixture was stirred overnight at RT.The reaction solution was filtered and the filtrate was concentrated togive 4-(ethylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (14 g, 93%yield). ¹H NMR (300 MHz, DMSO-d₆): δ 9.71 (s, 1H), 8.67 (br s, 1H), 8.49(s, 1H), 3.51 (m, 2H), 2.48 (s, 3H), 1.17 (t, J=7.2 Hz, 3H).

Example C6

A solution of isopropylamine in water (7.6 g, 0.13 mol) was addeddropwise to a solution of ethyl4-chloro-2-(methylthio)pyrimidine-5-carboxylate (15 g, 64.7 mmol) inCH₃CN (100 ml) at 0° C. The resulting mixture was stirred at RT for 8 h.The reaction was concentrated under reduced pressure and the residue waspartitioned between water and EtOAc.

The aqueous layer was extracted with EtOAc (3×50 mL) and the combinedorganics were washed with brine, dried (MgSO₄) and concentrated to giveethyl 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylate (16.4 g,99% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.51 (s, 1H), 8.05 (d, J=7.6Hz, 1H), 4.31-4.22 (m, 3H), 2.46 (s, 3H), 1.27 (t, J=7.2 Hz, 3H), 1.20(d, J=6.4 Hz, 6H).

To a solution of ethyl4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylate (16.4 g, 64.4mmol) in anhydrous THF (100 mL) was added LiAlH₄ (6.1 g, 0.16 mol) inportions at 0° C. under N₂ atmosphere. The reaction mixture was stirredan additional 30 min at RT and was quenched by the addition of water (6mL) followed by aqueous 2 N NaOH (6 mL). The suspension was filtered andthe filtrate was concentrated to give(4-(isopropylamino)-2-(methylthio)pyrimidin-5-yl)methanol (13.5 g, 98%yield), which was used without further purification. ¹H NMR (400 MHz,DMSO-d₆): δ 7.79 (s, 1H), 6.37 (d, J=7.6 Hz, 1H), 5.10 (t, J=5.6 Hz,1H), 4.28-4.20 (m, 3H), 2.38 (s, 3H), 1.13 (d, J=6.4 Hz, 6H).

Example C7

To a solution of ethyl 4,6-dichloronicotinate (5 g, 23 mmol) in CH₃CN(100 mL) was added dropwise a solution of isopropylamine in water (60%,4.5 g, 46 mmol) at 0° C. The resulting mixture was stirred at RT for 8h. The organic solution was removed under reduced pressure and theresidue was partitioned between water and EtOAc. The aqueous layer wasextracted with EtOAc (3×30 mL). The combined organics were washed withbrine, dried (MgSO₄) and concentrated to give ethyl6-chloro-4-(isopropylamino)nicotinate (5 g, 90% yield). ¹H NMR (300 MHz,DMSO-d₆): δ 8.51 (s, 1H), 7.97 (m, 1H), 6.82 (s, 1H), 4.27 (q, J=7.2 Hz,2H), 3.85 (m, 1H), 1.31 (t, J=7.2 Hz, 3H), 1.15 (d, J=6.3 Hz, 6H).

A mixture of ethyl 6-chloro-4-(isopropylamino)nicotinate (3.0 g, 12.4mmol), O,N-dimethylhydroxylamine hydrochloride (35.0 g, 0.35 mol) indioxane (10 mL) was heated at 180° C. for 6 h. After cooling to RT, thereaction mixture was neutralized with saturated Na₂CO₃ solution to pH7-8. The aqueous mixture was concentrated under reduced pressure and wasextracted with EtOAc (3×100 mL). The combined organics were washed withbrine, dried (MgSO₄) and concentrated to give ethyl4-(isopropylamino)-6-(methoxy(methyl)amino)nicotinate (3.2 g, 97%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.48 (s, 1H), 7.82 (d, J=7.2 Hz,1H), 6.10 (s, 1H), 4.22 (q, J=7.2 Hz, 2H), 3.77 (m, 4H), 3.18 (s, 3H),1.27 (t, J=7.2 Hz, 3H), 1.20 (d, J=6.4 Hz, 6H).

LiAlH₄ (0.9 g, 24.0 mmol) was added in portions to a solution of ethyl4-(isopropylamino)-6-(methoxy(methyl)amino)nicotinate (3.2 g, 12.0 mmol)in THF (60 mL) at 0° C. and the resultant reaction mixture was stirredat RT for 30 min. The reaction was quenched by the addition of water (1mL) and aqueous 2N NaOH (1 mL). The resulting precipitates were removedby filtration and the filtrate was concentrated to afford(4-(isopropylamino)-6-(methoxy(methyl)amino)pyridine-3-yl)methanol (2.9g, >100% yield), which was used without further purification. ¹HNMR (400MHz, DMSO-d₆): δ 7.62 (s, 1H), 6.16 (s, 1H), 5.44 (d, J=7.2 Hz, 1H),5.02 (bs, 1H), 4.33 (s, 2H), 3.69-3.61 (m, 4H), 3.06 (s, 3H), 1.18 (d,J=6.4 Hz, 6H).

Example C8

Using a procedure analogous to Example C7, ethyl 4,6-dichloronicotinate(20 g, 0.09 mol) and ethylamine (15.3 g, 0.22 mol) were combined toprovide (4-(ethylamino)-6-(methoxy(methyl)amino)pyridin-3-yl)methanol(16 g, 87% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 7.60 (s, 1H), 6.12 (s,1H), 5.64 (m, 1H), 4.92 (m, 1H), 4.31 (d, J=5.2 Hz, 2H), 3.63 (s, 3H),3.12 (q, J=7.2 Hz, 2H), 3.04 (s, 3H), 1.16 (t, J=7.2 Hz, 3H); MS (ESI)m/z: 211.9 [M+H]⁺.

Example D1

Concentrated nitric acid (17 g, 0.18 mol) was added dropwise to astirred solution of 4-fluoro-2-methylaniline (20 g, 0.16 mol) in coneH₂SO₄ (300 mL) at −10° C. The mixture was stirred at −10° C. for 10min., and the reaction mixture was poured into ice water. The resultantsolid was collected by filtration and partitioned between EtOAc and aqNa₂CO₃ solution (pH 8). The organic solution was washed with brine,dried (MgSO₄) and concentrated to give 4-fluoro-2-methyl-5-nitroaniline(20 g, 74% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 7.27 (d, J=6.8 Hz, 1H),7.14 (d, J=12.4 Hz, 1H), 5.37 (s, 2H), 2.10 (s, 3H).

Example D2

Concentrated nitric acid (8.8 g, 91 mmol) was added drop wise over 30min to a stirred solution of 2-chloro-4-fluoro-phenylamine (12 g, 82.3mmol) in cone H₂SO₄ acid (100 mL) at −10° C. The mixture was stirred atthat temperature for 10 min. Then the reaction mixture was poured intocooled EtOAc, and ice water was added. The organic layer was separatedand washed with brine and saturated NaHCO₃ solution, dried (MgSO4) andconcentrated in vacuo. Recrystallization (ethyl ether) provided2-chloro-4-fluoro-5-nitroaniline (5.0 g, 32% yield). ¹H NMR (400 MHz,DMSO-d₆): δ7.59 (d, J=11.2 Hz, 1H), 7.48 (d, J=7.2 Hz, 1H), 5.84 (s,2H).

Example D3

To a solution of 2,4-dichloro-5-nitropyrimidine (8 g, 41 mmol) in EtOHwas added dropwise a solution of methyl amine in EtOH (65%, 7.8 g, 0.164mmol) at −78° C., then the mixture was warmed to RT and stirredovernight. The precipitate was collected by filtration, and the yellowsolid was recrystallized (DMSO) to affordN2,N4-dimethyl-5-nitropyrimidine-2,4-diamine (6.5 g, 86% yield). ¹H NMR(400 MHz, DMSO-d₆): δ 8.98 (s, 0.3H), 8.90 (s, 0.7H), 8.72 (m, J=3.9 Hz,0.7H), 8.52 (s, br, 0.3H), 8.14 (m, 0.7H), 7.97 (m, 0.3H), 2.98 (d,J=4.8 Hz, 2.1H), 2.90 (d, J=3.9 Hz, 0.9H), 2.85 (d, J=3.9 Hz, 3H).

To a solution of N2,N4-dimethyl-5-nitropyrimidine-2,4-diamine (4 g, 21.8mmol) in EtOH was added 10% Pd/C (0.5 g) and 1 N aq HCl solution (10 mL,10 mmol). The mixture was hydrogenated (30 psi) for 2 h. The reactionmixture was filtered and the filtrate was concentrated to giveN2,N4-dimethylpyrimidine-2,4,5-triamine HCl (4 g, 97% yield). ¹H NMR(400 MHz, CD₃OD): δ 9.00 (s, 1H), 3.45 (s, 3H), 3.35 (s, 3H).

Example 1

To a solution of Example B1 (10.00 g, 46.4 mmol, 1.00 eq) and pyridine(7.58 ml, 92.9 mmol, 2.00 eq) in CH₂Cl₂ (225 ml) at 0° C. was addedisopropenyl chloroformate (5.33 ml, 4.8.8 mmol, 1.05 eq). After 45 minat 0° C., the completed reaction was washed with 3M HCl (2×), satd.NaHCO₃ (1×), and brine (1×), dried (MgSO₄), filtered and evaporated toafford crude product (14.9 g) as an oil that solidified on the pump. Thecrude material obtained was upgraded by triturating in warm (60° C.)hexanes (70 ml) for 20-30 min until a powdery precipitate was obtained.After cooling to RT, the solids were collected by filtration, rinsingforward with hexanes. The cake was washed with more hexanes and thendried on the filter to afford prop-1-en-2-yl3-t-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate (10.79 g, 78% yield) as atan powder which was used as is in the next reaction. MS (ESI) m/z:300.3 (M+H⁺).

Prop-1-en-2-yl 3-t-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate (0.100 g,0.334 mmol, 1.00 eq), Example A2 (0.0963 g, 0.334 mmol, 1.00 eq) and1-methylpyrrolidine (0.00174 ml, 0.0167 mmol, 0.05 eq) were combined inTHF (3.5 ml) and stirred with heating at 70° C. overnight. The completedreaction was cooled to RT and concentrated to a solid residue. This wastreated with CH₂Cl₂ to give a suspension which was thoroughly chilled inice. The solids were collected by filtration, rinsed well with ice-coldCH₂Cl₂ and dried on the filter to afford1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-t-butyl-1-phenyl-1H-pyrazol-5-yl)urea(0.1336 g, 76% yield) as a pale yellow solid. This was suspended inMeCN, treated with certified 0.1N HCl (2.52 ml, 1.0 eq) frozen andlyophilized to afford the HCl salt (0.1641 g) as a pale yellow solid. ¹HNMR (400 MHz, DMSO-d₆): δ 9.14 (brs, 1H), 8.99 (brs, 1H), 8.22-8.20 (m,1H), 8.04 (s, 1H), 7.58-7.51 (m, 4H), 7.47-7.42 (m, 1H), 7.34-7.29 (m,1H), 7.04-7.01 (m, 1H), 6.40 (s, 1H), 4.66 (s, 2H), 3.31 (s, 3H), 1.27(s, 9H); MS (ESI) m/z: 530.2 (M+H⁺).

Example 2

Using general method A, the TROC carbamate of Example B5 (0.100 g, 0.344mmol, 1.00 eq) and Example A2 (0.0877 g, 0.304 mmol, 1.00 eq) werecombined to afford1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-t-butyl-1-methyl-1H-pyrazol-5-yl)urea(44.4 mg, 31% yield) as a white solid which was converted to the HClsalt (48.0 mg). ¹H NMR (400 MHz, DMSO-d₆): δ 9.24 (s, 1H), 9.07 (brs,1H), 8.31 (dd, 1H, J=2.8 and 7.2 Hz), 8.04 (s, 1H), 7.34 (dd, 1H, J=8.80and 10.8 Hz), 7.03 (ddd, 1H, J=2.8, 4.40 and 8.80 Hz), 6.10 (s, 1H),4.67 (brs, 2H), 3.64 (s, 3H), 3.31 (s, 3H), 1.20 (s, 9H); MS (ESI) m/z:468.2 (M+H⁺).

Example 3

Using general method G, 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-amine(2.51 g, 11 mmol) and Example A3 (0.17 g, 0.55 mmol) were combined toafford1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)ureaas an off-white solid (0.145 g, 48%, yield). ¹H NMR (400 MHz, DMSO-d₆):δ 9.15 (s, 1H), 9.11 (d, J=2.0 Hz, 1H), 8.05 (dd, J=7.2 Hz, 2.8 Hz, 1H),7.91 (s, 1H), 7.58-7.52 (m, 5H), 7.21 (dd, J=10.8 Hz, 8.8 Hz, 1H),6.98-6.94 (m, 2H), 6.83 (s, 1H), 4.52 (s, 2H), 3.19 (s, 3H), 2.73 (d,J=4.4 Hz, 3H); MS (ESI) m/z: 556.3 (M+H⁺).

Example 4

Using general method B, prop-1-en-2-yl 3-tert-butylphenylcarbamate(0.070 g, 0.30 mmol) and Example A3 (0.0907 g, 0.30 mmol) were combinedto afford1-(3-tert-butylphenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea(0.030 g, 21% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆), δ 9.09(s, 1H), 8.59 (s, 1H), 8.18 (dd, J=7.6, 2.4 Hz, 1H), 7.98 (s, 1H), 7.47(s, 1H), 7.31-7.21 (m, 3H), 7.05-6.98 (m, 3H), 4.60 (s, 1H), 3.27 (s,3H), 2.81 (d, J=4.4 Hz, 3H), 1.27 (s, 9H); MS (ESI) m/z: 478.3 (M+H⁺).

Example 5

Using general method C, the carbamate of Example B2 (100 mg, 0.23 mmol)and Example A2 (65 mg, 0.23 mmol) were combined to provide1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea(76 mg, 58% yield). ¹H NMR (400 MHz, DMSO-d): δ 9.02 (s, 1H), 8.99 (m,1H), 8.95 (dd, J=4.2, 1.5 Hz, 1H), 8.48 (m, 1H), 8.17-8.10 (m, 3H), 7.92(dd, J=9.0. 2.4 Hz, 1H), 7.91 (s, 1H), 7.60 (dd, J=8.4, 4.3 Hz, 1H),7.23 (dd, J=11.0, 8.6 Hz, 1H), 6.97 (m, 1H), 6.55 (s, 2H), 6.46 (s, 1H),4.54 (s, 2H), 3.29 (s, 3H), 1.28 (s, 9H); MS (ESI) m/z: 581.3 (M+H⁺).

Example 6

Using general method C, the TROC carbamate of Example B3 (0.100 g, 0.317mmol) and Example A3 (0.0958 g, 0.317 mmol) were combined and purifiedby reverse phase chromatography (5-42% MeCN (w/0.1% TFA)/H₂O (w/0.1%TFA)) to afford1-(3-t-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea(62.7 mg, 42% yield) following lyophilization. ¹H NMR (400 MHz,DMSO-d₆): δ 10.41 (s, 1H), 8.87 (brs, 1H), 8.14 (dd, J=2.8 and 7.2 Hz,1H), 8.03 (s, 1H), 7.33 (dd, J=8.8 and 10.8 Hz, 1H), 7.07 (ddd, J=2.8,4.0, and 8.4 Hz, 1H), 6.04 (s, 1H), 4.65 (s, 2H), 3.31 (brs, 3H), 2.90(brs, 3H), 1.23 (s, 9H); MS (ESI) m/z: 469.2 (M+H⁺).

Example 7

Using general method B, the carbamate of Example B4 (0.15 g, 0.48 mmol)and Example A7 (0.15 g, 0.48 mmol) were combined to afford1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea(0.17 g, 62% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.20 (s, 1H), 9.15(brs, 1H), 8.09 (dd, J=2.8, and 7.6 Hz, 1H), 7.95 (s, 1H), 7.5-7.7 (m,5H), 7.26 (dd, J=8.8, and 10.8 Hz, 1H), 6.8-7.05 9m, 2H), 6.87 (s, 1H),4.55 (s, 3H), 3.94 (q, J=6.8 Hz, 2H), 2.77 (d, J=4.8 Hz, 3H), 1.16 (t,J=6.8 Hz, 3H); MS (ESI) m/z: 570.2 (M+H⁺).

Example 8

Using general method A, the TROC carbamate of Example B3 (0.35 g, 1.1mmol) and Example A6 (0.37 g, 1.1 mmol) were combined to afford1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylthio)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea(0.17 g, 31% yield). MS (ESI) m/z: 500.3 (M+H⁺).

Using a procedure analogous to ExampleA2,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylthio)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea(0.080 g, 0.16 mmol) was treated with mCPBA (70% wt, 0.10 g, 0.41 mmol)and then N-methylamine (2.0M in THF, 0.68 mL, 1.4 mmol) to afford3-(3-amino-4-fluorophenyl)-1-ethyl-7-(methylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one(0.14 g, 85% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.4 (s, 1H), 8.80 (d,J=2.4 Hz, 1H), 8.09 (dd, J=2.8, and 7.6 Hz, 1H), 7.96 (s, 1H), 7.29 (dd,J=8.8, and 10.8 Hz, 1H), 7.06 (m, 1H), 7.00 (m, 1H), 6.05 (s, 1H), 4.57(s, 3H), 3.95 (q, J=4.0 Hz, 2H), 2.78 (d, J=4.8 Hz, 3H), 1.23 (s, 9H),1.17 (t, J=4.0 Hz, 3H); MS (ESI) m/z: 483.3 (M+H⁺).

Example 9

Using general method B, the carbamate of 5-t-butylisoxazol-3-amine (58mg, 0.26 mmol) and Example A5 (0.080 g, 0.26 mmol) were combined toprovide1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropteridin-6-yl)phenyl)urea(41 mg, 34% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.74 and 8.57 (s, 1H),8.10 (d, J=8.4 Hz, 1H), 8.00 (br m, 1H), 7.24-7.12 (m, 2H), 6.44 (s,1H), 3.57 and 3.50 (s, 3H), 2.92 (br s, 3H), 2.28 (s, 3H), 1.26 (s, 9H);MS (ESI) m/z: 481.2 (M+H⁺).

Example 10

Using general method A, the TROC carbamate of B4 (0.21 g, 0.52 mmol) andExample A21 (0.2 g, 0.47 mmol) were combined to provide1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea(140 mg, 52% yield). ¹H NMR (400 MHz, DMSO-d₆) δ9.13 (brs, 2H), 8.03 (d,J=9 Hz, 1H), 7.93 (s, 1H), 7.64-7.51 (m, 5H), 7.18 (d, J=12 Hz, 1H),7.01 (m, 1H), 6.85 (s, 1H), 4.52 (d, J=14 Hz, 1H), 4.34 (d, J=14 Hz,1H), 3.23 (brs, 3H), 2.78 (d, J=5 Hz, 3H), 2.05 (s, 3H); MS (ESI, m/z:570.2, M+H⁺).

Example 11

Using general method A, the TROC carbamate of Example B3 (0.3 g, 0.95mmol) and Example A10 (0.3 g, 0.9 mmol) were combined to provide1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylthio)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea(220 mg, 46% yield). ¹H NMR (400 MHz, DMSO-d₆): δ10.32 (brs, 1H), 8.74(brs, 1H), 8.22 (s, 1H), 8.04 (d, J=8 Hz, 1H), 7.24 (d, J=12 Hz, 1H),6.03 (s, 1H), 4.70 (d, J=15 Hz, 1H), 4.52 (d, J=15 Hz, 1H), 3.27 (s,3H), 2.50 (s, 3H), 2.06 (s, 3H), 1.21 (s, 9H); MS (ESI) m/z: 500.3(M+H⁺).

Using a procedure analogous to ExampleA2,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylthio)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea(0.58 g, 1.2 mmol) and methylamine (1 ml, 3 mmol, 3.0M in THF) werecombined to provide1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea(0.995 g, 95% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.31 (brs, 1H), 8.73(s, 1H), 8.00 (d, J=9 Hz, 1H), 7.94 (brs, 1H), 7.23 (d, J=12 Hz, 1H),7.02 (m, 1H), 6.04 (s, 1H), 4.55 (d, J=14 Hz, 1H), 4.35 (d, J=14 Hz,1H), 3.24 (brs, 3H), 2.79 (d, J=5 Hz, 3H), 2.08 (s, 3H), 1.22 (s, 9H);MS (ESI) m/z: 483.3 (M+H⁺).

Example 12

Using general method A, the TROC carbamate of Example B5 (0.16 g, 0.47mmol) and Example A21 (0.15 g, 0.47 mmol) were combined to provide1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea(190 mg, 81% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.86 (brs, 2H), 8.05(d, J=9 Hz, 1H), 7.93 (s, 1H), 7.19 (d, J=12 Hz, 1H), 7.01 (m, 1H), 6.06(s, 1H), 4.54 (d, J=14 Hz, 1H), 4.35 (d, J=14 Hz, 1H), 3.59 (s, 3H),3.23 (brs, 3H), 2.78 (d, J=5 Hz, 3H), 2.05 (s, 3H), 1.17 (s, 9H); MS(ESI, m/z: 496.3, M+H⁺).

Example 13

Using general method C, the TROC carbamate of Example B3 (0.3 g, 0.95mmol) and Example A10 (0.3 g, 0.9 mmol) were combined to provide1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylthio)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea(0.22 g, 46% yield) 1H NMR (400 MHz, DMSO-d₆): δ 10.32 (brs, 1H), 8.74(brs, 1H), 8.22 (s, 1H), 8.04 (d, J=8 Hz, 1H), 7.24 (d, J=12 Hz, 1H),6.03 (s, 1H), 4.70 (d, J=15 Hz, 1H), 4.52 (d, J=15 Hz, 1H), 3.27 (s,3H), 2.50 (s, 3H), 2.06 (s, 3H), 1.21 (s, 9H); MS (ESI) m/z: 500.3(M+H⁺).

Using a procedure analogous to Example A2, oxidation of the sulfide withmCPBA followed by reaction with excess N,N-dimethylethylamine provided1-(3-tert-butylisoxazol-5-yl)-3-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)ureawhich was converted to methane sulfonic acid salt (52% yield) ¹H NMR(400 MHz, DMSO-d₆): δ10.35 (brs, 1H), 8.57 (brs, 1H), 8.02 (d, J=9 Hz,1H), 8.0 (s, 1H), 7.3 (m, 1H), 7.25 (d, J=12 Hz, 1H), 6.03 (s, 1H), 4.60(d, J=14 Hz, 1H), 4.40 (d, J=14 Hz, 1H), 3.60 (m, 2H), 3.20 (m, 2H),2.80 (s, 6H), 2.32 (s, 3H), 2.03 (s, 3H), 1.21 (s, 9H); MS (ESI) m/z:498.0 (M+H⁺).

Example 14

Using general method G, the carbamate of 5-t-butylisoxazol-3-amine(0.050 g, 0.223 mmol) and Example A21 (0.078 g, 0.245 mmol) werecombined to afford1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea(0.042 g, 39% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.82(s, 1H), 8.80 (s, 1H), 8.03 (d, J=7.6 Hz, 1H), 7.94 (s, 1H), 7.23 (d,J=12.0 Hz, 1H), 7.02 (m, 1H), 6.46 (s, 1H), 4.55 (d, J=13.6 Hz, 1H),4.36 (d, J=13.6 Hz, 1H), 3.24 (s, 3H), 2.79 (d, J=4.0 Hz, 3H), 2.07 (s,3H), 1.26 (s, 9H); MS (ESI) m/z: 483.3 (M+H⁺).

Example 15

Using general method F, 3-(trifluoromethyl)phenylisocyanate (41 mg, 0.22mmol) and Example A21 (70 mg, 0.22 mmol) in the presence of pyridine (36μL, 0.44 mmol) were combined to afford1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea(59 mg, 53% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.38 (s, 1H), 8.65 (d,J=2.0 Hz, 1H), 8.04 (m, 2H), 7.94 (brs, 1H), 7.48 (m, 2H), 7.31 (m, 1H),7.21 (d, J=12.4 Hz, 1H), 7.01 (q, J=4.8 Hz, 1H), 4.58 (d, J=14.0 Hz,1H), 4.35 (d, J=14.0 Hz, 1H), 3.24 (brs, 3H), 2.79 (d, J=4.8 Hz, 3H),2.07 (s, 3H); MS (ESI) m/z: 504.0 (M+H⁺).

Example 16

Using general method B, the carbamate of 5-t-butylisoxazol-3-amine (50mg, 0.22 mmol) and Example A23 (77 mg, 0.22 mmol) were combined toafford1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea(0.067 g, 59% yield). ¹H NMR (400 MHz, DMSO-d₆): §9.82 (s, 1H), 8.80(brs, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.94 (brs, 1H), 7.21 (d, J=12.0 Hz,1H), 6.99 (m, 1H), 6.47 (s, 1H), 4.99 (m, 1H), 4.52 (d, J=14.0 Hz, 1H),4.28 (d, J=14.0 Hz, 1H), 2.78 (d, J=4.8 Hz, 3H), 2.04 (s, 3H), 1.46 (d,J=6.4 Hz, 6H), 1.27 (s, 9H); MS (ESI) m/z: 511.2 (M+H⁺).

Example 17

Using general method C, the TROC carbamate of Example B3 (0.165 g, 0.523mmol) and Example A23 (0.120 g, 0.348 mmol) were combined to afford1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea(0.022 g, 12% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ10.32 (s, 1H), 8.74 (s, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.94 (s, 1H), 7.22(d, J=12.0 Hz, 1H), 7.00 (m, 1H), 6.05 (s, 1H), 5.00 (m, 1H), 4.52 (d,J=13.6 Hz, 1H), 4.28 (d, J=13.6 Hz, 1H), 2.78 (d, J=4.8 Hz, 3H), 2.05(s, 3H), 1.46 (d, J=6.4 Hz, 6H), 1.23 (s, 9H); MS (ESI) m/z: 511.2(M+H⁺).

Example 18

Using general method B, the carbamate of 5-t-butylisoxazol-3-amine (50mg, 0.22 mmol) and Example A22 (74 mg, 0.22 mmol) were combined toafford1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea(0.033 g, 30% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.86 (s, 1H), 8.86(brs, 1H), 8.08 (dd, J=2.8, and 7.2 Hz, 1H), 7.96 (brs, 1H), 7.27 (dd,J=8.8, and 10.8 Hz, 1H), 7.00 (m, 2H), 4.97 (m, 1H), 4.51 (s, 2H), 2.78(d, J=4.8 Hz, 1H), 1.47 (d, J=6.4 Hz, 6H), 1.27 (s, 9H); MS (ESI) m/z:497.2 (M+H⁺).

Example 19

Using general method D, Example B7 (0.041 g, 0.24 mmol) and Example A17(0.084 g, 0.24 mmol) in presence of triethylamine (0.1 g, 0.97 mmol) andDPPA (0.2 g, 0.73 mmol) were combined to afford1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)ureaas a white solid (0.037 g, 30% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.67(s, 1H), 8.48 (d, J=2.0 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.94 (s, 1H),7.81 (m, 1H), 7.38 (s, 1H), 7.16 (d, J=12.0 Hz, 1H), 6.98-6.97 (m, 1H),5.02-4.95 (m, 1H), 4.51 (d, J=13.6 Hz, 1H), 4.28 (d, J=13.6 Hz, 1H),2.78 (d, J=4.4 Hz, 3H), 2.02 (s, 3H), 1.47-1.44 (m, 15H); MS (ESI) m/z:510.2 (M+H⁺).

Example 20

Using general method D, Example B7 (0.051 g, 0.3 mmol) and Example A22(0.1 g, 0.3 mmol) in presence of triethylamine (0.12 g, 1.2 mmol) anddiphenylphospharyl azide (0.25 g, 0.9 mmol) were combined to afford1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)ureaas a white solid (0.045 g, 30% yield). ¹H NMR (400 MHz, DMSO-d): a 8.72(s, 1H), 8.56 (s, 1H), 8.11 (dd, J=7.6 Hz, 2.4 Hz, 1H), 7.96 (s, 1H),7.81 (s, 1H), 7.39 (s, 1H), 7.23 (dd, J=11.2 Hz, 8.8 Hz, 1H), 6.99-6.96(m, 1H), 6.94-6.89 (m, 1H), 5.00-4.93 (m, 1H), 4.49 (s, 2H), 2.77 (d,J=4.4 Hz, 3H), 1.46-1.44 (m, 15H); MS (ESI) m/z: 496.3 (M+H⁺).

Example 21

Using general method B, the carbamate of Example B5 (50 mg, 0.21 mmol)and Example A7 (67 mg, 0.21 mmol) were combined to afford1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea(0.060 g, 58% yield). ¹H NMR (400 MHz, DMSO-ds): δ 8.95 (s, 1H), 8.88(d, J=2.0 Hz, 1H), 8.13 (dd, J=3.2, and 7.6 Hz, 1H), 7.96 (s, 1H), 7.28(dd, J=8.8, and 11.2 Hz, 1H), 7.00 (m, 2H), 6.08 (s, 1H), 4.56 (s, 2H),3.93 (q, J=4.8 Hz, 2H), 3.60 (s, 3H), 2.78 (d, J=4.8 Hz, 3H), 1.18 (s,9H), 1.15 (t, J=4.8 Hz, 3H), 1.27 (s, 9H); MS (ESI) m/z: 496.3 (M+H⁺).

Example 22

Using general method B, the carbamate of Example B4 (70 mg, 0.22 mmol)and Example A4 (68 mg, 0.22 mmol) were combined to afford1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea(0.066 g, 53% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.20 (s, 1H), 9.14(brs, 1H), 8.08 (dd, J=2.8, and 7.2 Hz, 1H), 7.74 (s, 1H), 7.62 (m, 5H),7.24 (d, J=8.8, and 10.8 Hz, 1H), 6.97 (m, 1H), 6.87 (s, 1H), 6.42 (q,J=4.8 Hz, 1H), 5.95 (s, 1H), 4.57 (s, 2H), 3.15 (s, 3H), 2.75 (d, J=4.8Hz, 3H); MS (ESI) m/z: 555.2 (M+H⁺).

Example 23

Using a modified general method C, the TROC carbamate of Example B6 (128mg, 0.40 mmol) and Example A4 (118 mg, 0.39 mmol) in DMF (1 mL) wastreated with iPr₂NEt (0.070 mL, 0.40 mmol). The reaction mixture washeated to 100° C. for 4 days. The reaction was concentrated in vacuo andpurified by chromatography on reverse phase silica gel to provide1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea(54 mg, 28% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.72 (s, 1H), 8.53 (d,J=2.2 Hz, 1H), 8.13 (dd, J=7.3, 2.5 Hz, 1H), 7.80 (s, 1 H), 7.74 (s,1H), 7.38 (s, 1H), 7.22 (dd, J=11.3, 8.8 Hz, 1H), 6.90 (ddd, J=8.8, 4.3,2.8 Hz, 1H), 6.41 (q, J=4.8 Hz, 1H), 5.95 (s, 1H), 4.57 (s, 2H), 3.17(s, 3H), 2.75 (d, J=5.0 Hz, 3H), 1.46 (s, 9H); MS (ESI) m/z: 467.3(M+H⁺).

Example 24

Using general method B, the carbamate of Example B5 (0.050 g, 0.211mmol) and Example A16 (0.066 g, 0.211 mmol) were combined to afford1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea(0.061 g, 59% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.89(s, 1H), 8.80 (d, J=1.2 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.72 (s, 1H),7.19 (d, J=12.0 Hz, 1H), 6.41 (m, 1H), 6.07 (s, 1H), 5.95 (s, 1H), 4.56(d, J=13.6 Hz, 1H), 4.36 (d, J=14.0 Hz, 1H), 3.59 (s, 3H), 3.16 (s, 3H),2.75 (d, J=4.8 Hz, 3H), 2.04 (s, 3H), 1.18 (s, 9H); MS (ESI) m/z: 495.2(M+H⁺).

Example 25

Using general method C, the TROC carbamate of example B3 (0.080 g, 0.254mmol) and Example A16 (80 mg, 0.254 mmol) were combined to afford1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea.This was treated with methanesulfonic acid to afford1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)ureamesylate salt (58 mg, 40% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.3 (s,1H), 8.78 (brs, 1H), 8.13 (brs, 1H), 8.03 (d, J=7.6 Hz, 1H), 7.77 (s,1H), 7.25 (d, J=11.6 Hz, 1H), 6.26 (s, 1H), 6.03 (s, 1H), 4.66 (d,J=14.8 Hz, 1H), 4.49 (d, J=14.8 Hz, 1H), 3.25 (s, 3H), 2.90 (d, J=4.8Hz, 3H), 2.31 (s, 3H), 2.07 (s, 3H), 1.23 (s, 9H); MS (ESI) m/z: 482.2(M+H⁺).

Example 26

Using general method B, the carbamate of 5-t-butylisoxazol-3-amine (70mg, 0.31 mmol) and Example A16 (98 mg, 0.31 mmol) were combined toafford1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea.This was treated with methanesulfonic acid to afford1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)ureamesylate salt (38 mg, 20% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.84 (s,1H), 8.84 (brs, 1H), 8.34 (brs, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.77 (s,1H), 7.25 (d, J=12.4 Hz, 1H), 6.45 (s, 1H), 6.29 (s, 1H), 4.68 (d,J=15.2 Hz, 1H), 4.50 (d, J=15.2 Hz, 1H), 3.26 (s, 3H), 2.92 (d, J=4.8Hz, 3H), 2.29 (s, 3H), 2.07 (s, 3H), 1.27 (s, 9H); MS (ESI) m/z: 482.2(M+H⁺).

Example 27

Using general method D, Example B7 (0.051 g, 0.3 mmol) and Example A16(0.096 g, 0.3 mmol) in presence of triethylamine (0.092 g, 0.91 mmol)and diphenylphospharyl azide (0.16 g, 0.6 mmol) were combined to afford1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)ureaas a white solid (37 mg. 25% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.67(s, 1H), 8.47 (s, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.80 (s, 1H), 7.71 (s,1H), 7.38 (s, 1H), 7.15 (d, J=12.0 Hz, 1H), 6.43-6.40 (m, 1H), 5.94 (s,1H), 4.55 (d, J=13.6 Hz, 1H), 4.37 (d, J=13.6 Hz, 1H), 3.16 (s, 3H),2.75 (d, J=4.8 Hz, 3H), 2.03 (s, 3H), 1.46 (s, 9H), 1.20 (t, J=6.8 Hz,3H); MS (ESI) m/z: 481.2 (M+H⁺).

Example 28

Using general method C, the TROC carbamate of Example B3 (50 mg, 0.16mmol) and Example A18 (50 mg, 0.15 mmol) were combined to provide1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea(33 mg, 41% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.39 (s, 1H), 8.92 (s,1H), 8.21 (d, J=8.0 Hz, 1H), 7.73 (s, 1H), 7.65 (d, J=10.8 Hz, 1H), 6.44(q, J=4.7 Hz, 1H), 6.60 (s, 1H), 5.97 (s, 1H), 4.57 (d, J=13.6 Hz, 1H),4.43 (d, J=13.5 Hz, 1H), 3.17 (s, 3H), 2.76 (d, J=4.7 Hz, 3H), 1.22 (s,9H); MS (ESI) m/z: 502.0, 504.0 (M+H⁺).

DP-2711 Example 29

Using general method B, the carbamate of 5-t-butylisoxazol-3-amine (60mg, 0.27 mmol) and Example A17 (92 mg, 0.27 mmol) were combined toafford1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea(0.041 g, 30% yield). ¹H NMR (400 MHz, DMSO-Qd): δ 9.81 (s, 1H), 8.78(brs, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.73 (s, 1H), 7.18 (d, J=12.0 Hz,1H), 6.48 (s, 1H), 6.39 (q, J=4.8 Hz, 1H), 6.16 (s, 1H), 4.47 (q, J=13.6Hz, 1H), 4.32 (m, 1H), 4.27 (d, J=13.6 Hz, 1H), 2.75 (d, J=4.8 Hz, 3H),2.01 (s, 1H), 1.45 (m, 6H), 1.27 (s, 9H); MS (ESI) m/z: 510.2 (M+H⁺).

Example 20

Using general method C, the TROC cartbamate of Example B3 (0.076 g,0.242 mmol) and Example A17 (0.076 g, 0.22 mmol) were combined to afford1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea(0.025 g, 22% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ10.32 (s, 1H), 8.73 (s, 1H), 7.95 (d, J=7.2 Hz, 1H), 7.73 (s, 1H), 7.19(d, J=12.0 Hz, 1H), 6.40 (m, 1H), 6.16 (s, 1H), 6.06 (s, 1H), 4.47 (d,J=13.2 Hz, 1H), 4.33-4.25 (m, 2H), 2.75 (d, J=4.8 Hz, 3H), 1.99 (s, 3H),1.45 (t, J=4.8 Hz, 6H), 1.23 (s, 9H); MS (ESI) m/z: 510.2 (M+H⁺).

Example 31

Using general method D, Example B7 (0.051 g, 0.3 mmol) and Example A17(0.104 g, 0.3 mmol) in presence of triethylamine (0.092 g, 0.91 mmol)and DPPA (0.25 g, 0.9 mmol) were combined to afford1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)ureaas a white solid (42 mg. 27% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.67(s, 1H), 8.47 (s, 1H), 8.03 (d, J=7.6 Hz, 1H), 7.81 (s, 1H), 7.73 (s,1H), 7.38 (s, 1H), 7.13 (d, J=12.0 Hz, 1H), 6.42-6.39 (m, 1H), 6.15 (s,1H), 4.47 (d, J=13.6 Hz, 1H), 4.34-4.24 (m, 2H), 2.75 (d, J=4.8 Hz, 3H),1.99 (s, 3H), 1.46-1.45 (m, 15H); MS (ESI) m/z: 509.2 (M+H⁺).

Example 32

Using general method F, Example A18 (88 mg, 0.29 mmol) and1-isocyanato-3-(trifluoromethyl)benzene (63 mg, 0.34 mmol) were combinedand purified by chromatography on reverse phase silica gel to provide1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea(12 mg, 13% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.46 (s, 1H), 8.86 (s,1H), 8.27 (d, J=8.1 Hz, 1H), 8.05 (s, 1H), 7.73 (s, 1H), 7.63 (d, J=10.8Hz, 1H), 7.54-7.47 (m, 2H), 7.34 (d, J=6.8 Hz, 1H), 6.53 (m, 1H), 5.98(s, 1H), 4.61 (d, J=13.8 Hz, 1H), 4.44 (d, J=13.8 Hz, 1H), 3.18 (s, 3H),2.77 (d, J=4.7 Hz, 3H); MS (ESI) m/z: 523.0, 525.0 (M+H⁺).

Example 33

Using general method C, the TROC carbamate of Example B3 (0.158 g, 0.501mmol) and Example A22 (0.110 g, 0.334 mmol) were combined to afford1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea(0.056 g, 34% yield was as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ10.36 (s, 1H), 8.80 (d, J=2.4 Hz, 1H), 8.06 (dd, J=7.2, 2.4 Hz, 1H),7.96 (s, 1H), 7.29 (m, 1H), 7.05-6.98 (m, 2H), 6.06 (s, 1H), 4.97 (m,1H), 4.51 (s, 2H), 2.78 (d, J=4.4 Hz, 3H), 1.47 (t, J=6.4 Hz, 6H), 1.23(s, 9H); MS (ESI) m/z: 497.2 (M+H⁺).

Example 34

Using general method C, the TROC carbamate of3-isopropyl-1-phenyl-1H-pyrazol-5-amine (0.061 g, 0.16 mmol) and ExampleA18 (0.054 g, 0.16 mmol) were combined to afford1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)ureaas a white solid (24 mg, 26% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.16(s, 1H), 8.93 (s, 1H), 8.25 (d, J=8.0 Hz, 1H), 7.72 (s, 1H), 7.60 (d,J=10.8 Hz, 1H), 7.55-7.48 (m, 3H), 7.44-7.40 (m, 1H), 6.46-6.42 (m, 1H),6.34 (s, 1H), 5.96 (s, 1H), 4.56 (d, J=14.0 Hz, 1H), 4.43 (d, J=14.0 Hz,1H), 3.17 (s, 3H), 2.89-2.82 (m, 1H), 2.74 (d, J=4.8 Hz, 3H), 1.20 (d,J=6.8 Hz, 6H); MS (ESI) m/z: 564.0 (M+H⁺).

Example 35

Using general method B, the carbamate of Example B6 (0.096 g, 0.43 mmol)and Example A25 (0.080 g, 0.215 mmol) were combined to afford1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea(0.020 g, 17% yield) as a white solid. It was converted to correspondingbismethylate salt by reacting with MsOH (2.0 eq.). ¹H NMR (400 MHz,DMSO-d₆): δ 9.50 (s, 1H), 8.72 (s, 1H), 8.55 (s, 1H), 8.81 (d, J=7.6 Hz,1H), 7.85 (s, 1H), 7.78 (s, 1H), 7.41 (s, 1H), 7.20 (d, J=12.0 Hz, 1H),6.33 (s, 1H), 4.70 (d, J=14.4 Hz, 1H), 4.52 (d, J=14.4 Hz, 1H), 3.72 (m,2H), 3.34-3.28 (m, 5H), 2.85 (s, 6H), 2.32 (s, 6H), 2.05 (s, 3H), 1.47(s, 9H); MS (ESI) m/z: 538.3 (M+H⁺).

Example 36

Using general method C, the TROC carbamate of Example B3 (0.080 g, 0.254mmol) and Example A19 (89 mg, 0.254 mmol) were combined to afford1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea(0.040 g, 32% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.3 (s, 1H), 8.72(s, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.72 (s, 1H), 7.21 (d, J=12.0 Hz, 1H),6.39 (q, J=4.4 Hz, 1H), 6.05 (s, 1H), 6.01 (s, 1H), 4.58 (d, J=13.6 Hz,1H), 4.34 (d, J=13.6 Hz, 1H), 3.77 (m, 2H), 2.76 (d, J=4.4 Hz, 3H), 2.04(s, 3H), 1.23 (s, 9H), 1.16 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 496.3(M+H⁺).

Example 37

Using general method C, the TROC carbamate of Example B3 (0.080 g, 0.254mmol) and Example A20 (89 mg, 0.254 mmol) were combined to afford1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea(0.030 g, 23% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.4 (s, 1H), 8.91(s, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.73 (s, 1H), 7.64 (d, J=10.8 Hz, 1H),6.41 (q, J=4.8 Hz, 1H), 6.06 (s, 1H), 6.03 (s, 1H), 4.58 (d, J=13.2 Hz,1H), 4.41 (d, J=13.2 Hz, 1H), 3.78 (m, 2H), 2.76 (d, J=4.8 Hz, 3H), 1.23(s, 9H), 1.16 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 516.0 (M+H⁺).

Example 38

Using general method F, 1-isocyanato-3-(trifluoromethyl)benzene (0.170g, 0.911 mmol) and Example A19 (0.250 g, 0.759 mmol) were combined toprovide1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)ureawhich was converted to the mesylate salt (0.130 g, 33.2% yield). ¹H NMR(400 MHz, DMSO-d₆): δ 9.49 (s, 1H), 8.76 (brs, 1H), 8.36 (brs, 1H), 8.09(m, 2H), 7.78 (s, 1H), 7.49 (m, 2H), 7.31 (m, 1H), 7.21 (d, J=12.5 Hz,1H), 6.38 (s, 1H), 4.74 (d, J=15 Hz, 1H), 4.48 (d, J=15 Hz, 1H), 3.87(m, 2H), 2.92 (d, J=6 Hz, 3H), 2.32 (s, 3H), 2.05 (s, 3H), 1.21 (t, J=6Hz, 3H); MS (ESI) m/z: 517.0 (M+H⁺).

Example 39

Using general method B, the carbamate of Example B1 (0.500 g, 1.670mmol) and Example A10 (0.557 g, 1.670 mmol) was combined to furnish1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylthio)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea(0.64 g, 66.7% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.01 (s, 1H), 8.89(s, 1H), 8.23 (s, 1H), 8.09 (d, J=8 Hz, 1H), 7.52 (m, 4H), 7.41 (m, 1H),7.19 (d, J=12 Hz, 1H), 6.37 (s, 1H), 4.70 (d, J=15 Hz, 1H), 4.52 (d,J=15 Hz, 1H), 3.28 (s, 3H), 2.51 (s, 3H), 2.06 (s, 3H), 1.24 (s, 9H); MS(ESI) m/z: 575.2 (M+H⁺).

Using a procedure analogous to Example A2, the sulfide was oxidized withmCPBA to the sulfone and then treated with methylamine to provide1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea(0.163 g, 66% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.98 (s, 1H), 8.85(brs, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.94 (s, 1H), 7.52 (m, 3H), 7.42 (m,1H), 7.18 (d, J=12 Hz, 1H), 7.02 (m, 1H), 6.38 (s, 1H), 4.53 (d, J=14Hz, 1H), 4.33 (d, J=14 Hz, 1H), 3.25 (brs, 3H), 2.78 (d, J=5 Hz, 3H),2.04 (s, 3H), 1.25 (s, 9H); MS (ESI) m/z: 558.3 (M+H⁺).

Example 40

Using general method C, the TROC carbamate of Example B2 (0.400 g, 0.906mmol) and Example A10 (0.302 g, 0.906 mmol) were combined to provide1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylthio)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea(0.49 g, 86% yield). ¹HNMR (400 MHz, DMSO-d₆): δ59.03 (s, 1H), 8.96 (m,2H), 8.48 (brd, J=9 Hz, 1H), 8.23 (s, 1H), 8.18 (s, 1H), 8.15 (m, 1H),8.09 (d, J=8 Hz, 1H), 7.93 (dd, J=9, 2.5 Hz, 1H), 7.60 (dd, J=9, 5 Hz,1H), 7.18 (d, J=12 Hz, 1H), 6.45 (s, 1H), 4.70 (d, J=15 Hz, 1H), 4.52(d, J=15 Hz, 1H), 3.28 (s, 3H), 2.51 (s, 3H), 2.06 (s, 3H), 1.28 (s,9H); MS (ESI) m/z: 626.3.3 (M+H⁺).

Using a procedure analogous to Example A2, the sulfide was oxidized withmCPBA to the sulfone and then treated with methylamine to provide1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea.¹H NMR (400 MHz, DMSO-d₆): 8.95 (m, 2H), 8.48 (m, 1H), 8.15 (m, 1H),8.04 (d, J=8 Hz, 1H), 7.92 (m, 2H), 7.60 (dd, J=8, 5 Hz, 1H), 7.17 (d,J=12 Hz, 1H), 7.02 (m, 1H), 6.46 (s, 1H), 4.53 (d, J=14 Hz, 1H), 4.33(d, J=14 Hz, 1H), 3.25 (brs, 3H), 2.78 (d, J=5 Hz, 3H), 2.04 (s, 3H),1.28 (s, 9H); MS (ESI) m/z: 609.2 (M+H⁺).

Example 41

Using general method F, 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene(0.191 g, 0.861 mmol) and Example A1 (0.250 g, 0.783 mmol) were combinedto provide1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-methyl-7-(methylthio)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea{0.29 g, 69% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.53 (s, 1H), 8.77(brs, 1H), 8.26 (s, 1H)), 8.13 (m, 2H), 7.61 (d, J=9 Hz, 1H), 7.55 (dd,J=9, 2.5 Hz, 1H), 7.30 (dd, J=12, 9 Hz, 1H), 7.04 (m, 1H), 4.74 (s, 2H),3.28 (s, 3H), 2.51 (s, 3H); MS (ESI) m/z: 541.0 (M+H⁺).

Using a procedure analogous to ExampleA2,1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-methyl-7-(methylthio)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)ureawas oxidized with mCPBA to the sulfone and then treated with methylamineto provide1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea(0.045 g, 16% yield). ¹H NMR (400 MHz, DMSO-d₆: δ 9.55 (s, 1H), 8.77 (s,1H), 8.12 (d, J=2.5 Hz, 1H)), 8.09 (dd, J=8, 2.5 Hz, 1H), 7.96 (brs,1H), 7.59 (m, 2H), 7.28 (dd, J=12.9 Hz, 1H), 7.01 (m, 2H), 5.74 (s, 1H),4.58 (s, 2H), 3.28 (brs, 3H), 2.78 (d, J=5 Hz, 3H); MS (ESI) m/z: 524.0(M+H⁺)

Example 42

Using general method F, 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene(0.159 g, 0.720 mmol) and Example A9 (0.250 g, 0.720 mmol) were combinedto provide1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-isopropyl-7-(methylthio)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea(0.37 g, 90% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.53 (s, 1H), 8.77(brs, 1H)), 8.26 (s, 1H)), 8.11 (d, J=2.5 Hz, 1H), 8.09 (dd, J=9, 2.5Hz, 1H), 7.61 (d, J=9 Hz, 1H), 7.56 (dd, J=9, 2.5 Hz, 1H), 7.29 (dd,J=12, 9 Hz, 1H), 7.03 (m, 1H), 4.97 (m, 1H), 4.68 (s, 2H), 2.51 (s, 3H),1.47 d, J=6 Hz, 6H); MS (ESI) m/z: 569.0 (M+H⁺).

Using a procedure analogous to Example A2, oxidation with MCPBA tosulfone followed by reaction with methylamine provided1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea(0.265 g, 74% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.12 (s, 1H), 8.03(dd, J=8, 2.5 Hz, 1H), 7.96 (brs, 1H), 7.58 (brs, 1H), 7.25 (dd, J=12, 9Hz, 1H), 6.97 (m, 2H), 4.98 (m, 1H), 4.52 (s, 2H), 2.78 (brs 3H), 1.47(d, J=6 Hz, 6H); MS (ESI) m/z: 552.2 (M+H⁺).

Example 43

Using general method B, the carbamate of3-isopropyl-1-phenyl-1H-pyrazol-5-amine (0.244 g, 0.861 mmol) andExample A1 (0.250 g, 0.783 mmol) were combined to provide1-(2-fluoro-5-(1-methyl-7-(methylthio)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea.¹H NMR (400 MHz, DMSO-d₆): δ 9.06 (brs, 1H), 8.92 (s, 1H), 8.25 s, 1H),8.16 (dd, J=8, 2.5 Hz, 1H)), 7.51 (m, 3H), 7.42 (m, 2H), 7.27 (dd, J=11,8 Hz, 1H), 7.00 (m, 1H), 6.33 (s, 1H), 4.72 (s, 2H), 3.28 (s, 3H), 2.86(m, 1H), 2.52 (s, 3H), 1.20 (d, J=6 Hz, 6H); MS (ESI) m/z: 547.0 (M+H⁺).

Using a procedure analogous to Example A2, the sulfide was oxidized withmCPBA to the sulfone and treated with methylamine to provide1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea(74% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.05 (s, 1H), 8.13 (dd, J=8,2.5 Hz, 1H), 7.96 (brs, 1H), 7.52 (m, 4H), 7.42 (m, 1H), 7.25 (dd,J=12.9 Hz, 1H), 7.00 (m, 2H), 6.34 (s, 1H), 4.56 (s, 2H), 3.25 (brs,3H), 2.86 (m, 1H), 2.78 (d, J=5 Hz, 3H), 1.20 (d, J=6 Hz, 6H); MS (ESI)m/z: 530.2 (M+H⁺).

Example 44

Using general method B, the carbamate of Example B6 (0.375 g, 1.696mmol) and Example A15 (0.400 g, 1.131 mmol) were combined to provide1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylthio)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea(0.32 g, 55% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.77 (brs, 1H), 8.73(brs, 1H)), 8.36 (d, J=9 Hz, 1H)), 8.25 (s, 1H), 7.81 (s, 1H), 7.62 (d,J=11 Hz, 1H), 7.40 (s, 1H), 4.72 (d, J=14 Hz, 1H), 4.56 (d, J=14 Hz,1H), 3.31 (s, 3H), 2.52 (s, 3H), 1.46 (s, 9H); MS (ESI) m/z: 519.2(M+H⁺).

Using a procedure analogous to Example A2, the sulfide was oxidized withmCPBA to the sulfone and then treated with methylamine to provide1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea(0.448 mmol, 73% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.76 (s, 1H), 8.72(brs, 1H), 8.32 (d, J=8.5 Hz, 1H), 7.96 (brs, 1H), 7.82 (s, 1H), 7.60(d, J=111 Hz, 1H), 7.41 (s, 1H), 7.04 m, 1H), 6.34 s, 1H), 4.56 (d, J=14Hz, 1H), 4.41 (d, J=14 Hz, 1H), 3.25 (brs, 3H), 2.78 (d, J=5 Hz, 3H),1.47 (m, 9H); MS (ESI) m/z: 502.2 (M+H⁺).

Example 45

Using general method F, 1-isocyanato-3-(trifluoromethyl)benzene (0.122g, 0.652 mmol) and Example A14 (0.2 g, 0.544 mmol) were combined toprovide to provide1-(4-chloro-5-(1-ethyl-7-(methylthio)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea(0.2 g, 66% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.46 (s, 1H), 8.88 brs,1H)), 8.36 (d, J=9 Hz, 1H), 8.25 (s, 1H), 8.09 (s, 1H), 7.66 (d, J=11Hz, 1H), 7.50 (m, 2H), 7.33 (m, 1H), 4.78 (d, J=14 Hz, 1H), 4.54 (d,J=14 Hz, 1H), 3.97 (m, 2H), 2.52 (s, 3H), 1.66 (d, J=6 Hz, 3H); MS (ESI)mni/z: 555.0 (M+H⁺).

Using a procedure analogous to Example A2, the sulfide was oxidized withmCPBA to the sulfone and then treated with methylamine to provide1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea(0.279 mmol, 88% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.51 (s, 1H), 8.32(d, J=8.0 Hz, 1H), 8.06 (s, 1H), 7.96 (brs, 1H), 7.87 (s, 1H), 7.64 (d,J=11 Hz, 1H), 7.50 (m, 2H), 7.33 (m, 1H), 7.02 (m, 1H), 4.60 (d, J=14Hz, 1H), 4.40 (d, J=14 Hz, 1H), 3.95 (m, 2H), 2.78 (d, J=5 Hz, 3H), 1.15(t, 3H); MS (ESI) m/z: 538.3 (M+H⁺).

Example 46

Using general method D, Example B8 (80 mg, 0.437 mmol), triethylamine(51 mg, 0.502 mmol), Example A17 (150 mg, 0.437 mmol) and DPPA (138 mg,0.502 mmol) were combined to afford1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea(35 mg, 15% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 1.44 (t, 6H), 1.52 (s,9H), 1.99 (s, 3H), 2.29 (s, 3H), 2.76 (m, 3H), 4.31 (hep, 1H), 4.39 (dof d, 2H), 6.18 (s, 1H), 6.60 (br. s, 1H), 7.14 (d, 1H), 7.42 (s, 1H),7.73 (s, 1H), 8.02 (d, 1H), 8.13 (s, 1H), 8.52 (br. s, 1H); MS (ESI)m/z: 523.2 (M+H⁺).

Example 47

Using general method B, the carbamate of Example B9 (0.078 g, 0.332mmol) and Example A21 (0.070 g, 0.221 mmol) were combined to afford1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea(0.064 g, 59%) as light yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 11.00(s, 1H), 8.88 (d, J=1.2 Hz, 1H), 7.94-7.92 (m, 2H), 7.26 (d, J=11.6 Hz,1H), 7.02 (m, 1H), 6.48 (s, 1H), 4.56 (d, J=14.0 Hz, 1H), 4.36 (d,J=14.0 Hz, 1H), 3.24 (s, 3H), 2.79 (d, J=4.8 Hz, 3H), 2.08 (s, 3H); MS(ESI) m/z: 495.0 (M+H⁺).

Example 48

Using general method B, Example B9 (0.066 g, 0.281 mmol) and Example A27(0.070 g, 0.187 mmol) were combined to afford1-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea(0.039 g, 38%) as a light yellow solid. It was converted tocorresponding mesylate salt by reacting with MsOH (1.0 eq.). ¹H NMR (400MHz, DMSO-d₆): δ 8.97 (s, 1H), 8.00 (s, 1H), 7.93 (d, J=7.6 Hz, 1H),7.29-7.25 (m, 2H), 6.47 (s, 1H), 4.60 (d, J=14.0 Hz, 1H), 4.40 (d,J=14.0 Hz, 1H), 3.56 (m, 2H), 3.26 (s, 3H), 3.15 (m, 2H), 2.74 (s, 6H),2.31 (s, 3H), 2.09 (s, 3H); MS (ESI) m/z: 552.2 (M+H⁺).

Example 49

Using general method B, the carbamate of Example B5 (60 mg, 0.25 mmol)and Example A26 (80 mg, 0.25 mmol) were combined to afford1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea(43 mg, 34% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.94 (s, 1H), 8.86(brs, 1H), 8.10 (dd, J=2.4, and 7.2 Hz, 1H), 7.74 (s, 1H), 7.26 (dd,J=8.8, and 11.2 Hz, 1H), 6.96 (m, 1H), 6.41 (q, J=4.8 Hz, 1H), 6.08 (s,1H), 6.02 (s, 1H), 4.56 (s, 2H), 3.78 (q, J=7.2 Hz, 2H), 3.60 (s, 3H),2.75 (q, J=4.8 Hz, 2H), 1.18 (s, 9H), 1.17 (t, J=7.2 Hz, 3H); MS (ESI)m/z: 495.2 (M+H⁺).

Example 50

Using general method C, the TROC carbamate of Example B3 (80 mg, 0.25mmol) and Example A26 (80 mg, 0.25 mmol) were combined to afford1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea(31 mg, 25% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.4 (s, 1H), 8.79(brs, 1H), 8.06 (dd, J=2.8, and 7.2 Hz, 1H), 7.75 (s, 1H), 7.27 (dd,J=8.8, and 10.8 Hz, 1H), 7.02 (m, 1H), 6.40 (q, J=4.4 Hz, 1H), 6.06 (s,1H), 6.02 (s, 1H), 4.57 (s, 2H), 3.78 (q, J=7.2 Hz, 2H), 2.75 (q, J=4.4Hz, 2H), 1.23 (s, 9H), 1.18 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 482.2(M+H⁺).

Example 51

Using general method D, Example B7 (0.051 g, 0.3 mmol) and Example A26(0.096 g, 0.3 mmol) in presence of triethylamine (0.09 g, 0.9 mmol) andDPPA (0.125 g, 0.45 mmol) were combined to afford1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)ureaas a white solid (0.028 g, 19% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.73(s, 1H), 8.55 (s, 1H), 8.13 (dd, J=7.6 Hz, 2.8 Hz, 1H), 7.82 (s, 1H),7.76 (s, 1H), 7.41 (s, 1H), 7.23 (dd, J=11.2 Hz, 10.8 Hz, 1H), 6.96-6.92(m, 1H), 6.41-6.38 (m, 1H), 6.03 (s, 1H), 4.57 (s, 2H), 3.82-3.77 (m,2H), 2.77 (d, J=4.4 Hz, 3H), 1.49 (s, 9H), 1.19 (t, J=6.8 Hz, 3H); MS(ESI) m/z: 481.2 (M+H⁺).

Example 52

Using general method B, Example B9 (0.066 g, 0.281 mmol) and Example A25(0.070 g, 0.187 mmol) were combined to afford1-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea(0.0304 g, 29%) as a white solid. It was converted to correspondingmesylate salt by reacting with MsOH (1.0 eq.). ¹H NMR (400 MHz,DMSO-d₆): δ 11.08 (s, 1H), 8.99 (s, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.83(s, 1H), 7.28 (d, J=12.0 Hz, 1H), 6.46 (s, 1H), 6.23 (s, 1H), 4.67 (d,J=14.4 Hz, 1H), 4.47 (d, J=14.4 Hz, 1H), 3.66 (m, 2H), 3.28-3.23 (m,5H), 2.84 (s, 6H), 2.33 (s, 3H), 2.07 (s, 3H); MS (ESI) m/z: 551.2(M+H⁺).

Example 53

Using general method B, prop-1-en-2-yl5-tert-butyl-1,3,4-thiadiazol-2-ylcarbamate (55.9 mg, 0.232 mmol) andExample A3 (70 mg, 0.232 mmol) were combined and purified directly byreverse phase chromatography (MeCN (w/0.1% TFA)/H₂O (w/0.1% TFA)) toafford1-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea(37 mg, 33% yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ9.04 (brs, 1H), 8.14-8.12 (m, 1H), 8.03 (s, 1H), 7.38-7.33 (m, 1H),7.11-7.07 (m, 1H), 4.66 (s, 2H), 3.31 (brs, 3H), 2.90 (brs, 3H), 1.37(s, 9H); MS (ESI) m/z: 486.0 (M+H⁺).

Example 54

Using general method F, 1-isocyanatonaphthalene (0.05 g, 0.3 mmol) andexample A19 (0.1 g, 0.3 mmol) were combined to afford1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(naphthalen-1-yl)ureaas a white solid (0.032 g, 21% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.19(s, 1H), 9.12 (s, 1H), 8.19 (t, J=8.0 Hz, 2H), 8.08 (d, J=7.6 Hz, 1H),7.98 (d, J=8.0 Hz, 1H), 7.78 (s, 1H), 7.69-7.58 (m, 3H), 7.50 (t, J=8.0Hz, 1H), 7.27 (d, J=12.0 Hz, 1H), 6.47-6.44 (m, 1H), 6.06 (s, 1H), 4.66(d, J=14.0 Hz, 1H), 4.42 (d, J=14.0 Hz, 1H), 3.87-3.78 (m, 2H), 2.81 (d,J=4.8 Hz, 3H), 2.10 (s, 3H), 1.21 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 499.2(M+H⁺).

Example 55

Using general method F, 1-isocyanatonaphthalene (0.05 g, 0.31 mmol) andExample A26 (0.1 g, 0.31 mmol) were combined to afford1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)ureaas a white solid (0.061 g, 40% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.24(s, 1H), 9.19 (s, 1H), 8.26 (dd, J=7.2 Hz, 2.8 Hz, 1H), 8.21 (d, J=8.4Hz, 1H), 8.08 (dd, J=11.6 Hz, 0.8 Hz, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.81(s, 1H), 7.71-7.58 (m, 4H), 7.52 (t, J=8.0 Hz, 1H), 7.05-7.01 (m, 1H),6.46 (q, J=4.8 Hz, 1H), 6.08 (s, 1H), 4.64 (s, 2H), 3.84 (q, J=6.8 Hz,2H), 2.81 (d, J=4.8 Hz, 3H), 1.24 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 485.0(M+H⁺).

Example 56

Using general method F, 1-isocyanatonaphthalene (0.05 g, 0.3 mmol) andExample A32 (0.105 g, 0.3 mmol) were combined to afford1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)ureaas a white solid (0.059 g, 38% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.33(brs, 2H), 8.41 (d, J=8.0 Hz, 1H), 8.20 (d, J=8.0 Hz, 1H), 8.06 (d,J=6.8 Hz, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.78 (s, 1H), 7.71-7.58 (m, 4H),7.51 (t, J=8.0 Hz, 1H), 6.46 (q, J=4.8 Hz, 1H), 6.08 (s, 1H), 4.65 (d,J=13.6 Hz, 1H), 4.48 (d, J=13.6 Hz, 1H), 3.84-3.80 (m, 2H), 2.81 (d,J=4.8 Hz, 3H), 1.21 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 519.0 (M+H⁺).

Example 57

Using general method D, Example B10 (70 mg, 0.19 mmol) and Example A3(58 mg, 0.19 mmol) in presence of DPPA (55 μL, 0.21 mmol) and Et₃N (30μL, 0.21 mmol) were combined to afford tert-butyl4-(2-tert-butyl-5-(3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)ureido)pyrimidin-4-yl)piperazine-1-carboxylate(32 mg, 25% yield) which was treated with HCl (4.0 M, in dioxane) toafford1-(2-tert-butyl-4-(piperazin-1-yl)pyrimidin-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)ureaHCl salt (24 mg, 88% yield). ¹H NMR (400 MHz, DMSO-d₆, major isomer): δ9.60 (brs, 1H), 9.54 (brs, 2H), 8.62 (s, 1H), 8.54 (brs, 1H), 8.21 (dd,J=2.4, and 7.2 Hz, 1H), 8.18 (s, 1H), 7.41 (dd, J=9.2, and 10.8 Hz, 1H),7.13 (m, 1H), 4.76 (s, 2H), 4.07 (brm, 4H), 3.46 (brs, 3H), 3.35 (brm,4H), 3.03 (brs, 3H), 1.45 (s, 9H); MS (ESI) m/z: 564.3 (M+H⁺).

Example 58

Using general method F, 1-isocyanato-3-(trifluoromethyl)benzene (0.05 g,0.267 mmol) and Example A28 (0.088 g, 0.267 mmol) were combined toprovide1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea(0.11 g, 80%). ¹H NMR (400 MHz, DMSO-d₆): δ 9.48 (s, 1H), 8.76 (s, 1H),8.09 (m, 2H), 7.82 (s, 1H), 7.56 (m, 2H), 7.38 (m, 1H), 7.29 (m, 1H),7.0 (m, 1H), 6.42 (m, 1H), 6.22 (s, 1H), 4.55 (s, 2H), 4.37 (m, 1H),2.81 (d, J=5 Hz, 3H), 1.52 (d, J=6 Hz, 6H); MS (ESI) m/z: 517.0 (M+H⁺).

Example 59

Using general method F, 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene(70 mg, 0.32 mmol) and Example A4 (95 mg, 0.32 mmol) were combined toafford1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea(91 mg, 64% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.58 (s, 1H), 8.80 (s,1H), 8.18 (d, J=2.0 Hz, 1H), 8.13 (dd, J=2.8, and 7.6 Hz, 1H), 7.81 (s,1H), 7.68 (d, J=8.4 Hz, 1H), 7.63 (dd, J=2.4, and 8.4 Hz, 1H), 7.33 (dd,J=8.8, and 10.8 Hz, 1H), 7.06 (m, 1H), 6.48 (q, J=4.8 Hz, 1H), 6.03 (s,1H), 4.66 (s, 2H), 3.25 (s, 3H), 2.82 (d, J=4.8 Hz, 3H); MS (ESI) m/z:523.0 (M+H⁺).

Example 60

To a stirring suspension of Example A26 (100 mg, 0.317 mmol) in CH₂Cl₂(3.036 ml), thoroughly cooled to 0° C., was rapidly added 20% COCl₂ inPhMe (0.184 ml, 0.349 mmol).

After 10 min at 0° C., the reaction was then treated with Et₃N (0.133ml, 0.951 mmol). After another 10 min at 0° C., cyclohexylamine (0.040ml, 0.349 mmol) was added and the reaction was stirred for 72 h at RT.The crude reaction mixture was purified directly by flash columnchromatography (100% CH₂Cl₂ to 30% THF/CH₂Cl₂). The still impure productwas re-purified by reverse phase chromatography (MeCN (w/0.1% TFA)/H₂O(w/0.1% TFA)) to afford a white solid. The TFA salt thus obtained wasdissolved in THF and converted to the free base with MP-Carbonate resinto afford1-cyclohexyl-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea(15 mg, 12% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.23(brs, 1H), 8.05 (s, 1H), 7.02-6.97 (m, 1H), 6.86 (s, 1H), 6.73-6.68 (m,2H), 6.49-6.46 (m, 1H), 4.68 (s, 2H), 3.89 (q, J=6.8 Hz, 2H), 3.57 (m,1H), 1.83-1.77 (m, 2H), 1.64-1.60 (m, 2H), 1.55-1.47 (m, 1H), 1.34-1.17(m, 8H); MS (ESI) m/z: 441.2 (M+H⁺).

Example 61

Using general method B, the carbamate of 5-t-butylisoxazol-3-amine (58mg, 0.26 mmol) and Example A5 (0.080 g, 0.26 mmol) were combined toprovide1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropteridin-6-yl)phenyl)urea(41 mg, 34% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.74 and 8.57 (s, 1H),8.10 (d, J=8.4 Hz, 1H), 8.00 (br m, 1H), 7.24-7.12 (m, 2H), 6.44 (s,1H), 3.57 and 3.50 (s, 3H), 2.92 (br s, 3H), 2.28 (s, 3H), 1.26 (s, 9H);MS (ESI) m/z: 481.2 (M+H⁺).

Example 62

Using general method F, 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene(70 mg, 0.32 mmol) and Example A4 (95 mg, 0.32 mmol) in presence ofpyridine (51 μL, 0.63 mmol) were combined to afford1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea(93 mg, 56% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.58 (s, 1H), 8.80 (s,1H), 8.18 (d, J=2.0 Hz, 1H), 8.13 (dd, J=2.8, and 7.6 Hz, 1H), 7.81 (s,1H), 7.68 (d, J=8.4 Hz, 1H), 7.63 (dd, J=2.4, and 8.4 Hz, 1H), 7.33 (dd,J=8.8, and 10.8 Hz, 1H), 7.06 (m, 1H), 6.48 (q, J=4.8 Hz, 1H), 6.03 (s,1H), 4.66 (s, 2H), 3.25 (s, 3H), 2.82 (d, J=4.8 Hz, 3H); MS (ESI) m/z:523.0 (M+H⁺).

Example 63

Using General Method F, Example A28 (100 mg, 0.304 mmol), cyclohexylisocyanate (0.078 mL, 0.611 mmol) and pyridine (0.493 mL, 0.611 mmol)were reacted to afford1-cyclohexyl-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea(30 mg, 22% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.27(d, J=2.8 Hz, 1H), 8.11 (dd, J=2.8 and 7.6 Hz, 1H), 7.79 (s, 1H), 7.19(dd, J=8.8 and 11.2 Hz, 1H), 6.86 (s, 1H), 6.85-6.81 (m, 1H), 6.66-6.64(m, 1H), 6.38 (brs, 1H), 4.55 (s, 2H), 4.39 (septet, J=6.8 Hz, 1H),3.47-3.39 (m, 1H), 2.85 (d, J=4.4 Hz, 3H), 1.79-1.75 (m, 2H), 1.66-1.58(m, 2H), 1.52-1.46 (m, 1H), 1.46 (d, J=6.8 Hz, 6H), 1.31-1.07 (m, 5H);MS (ESI) m/z: 455.3 (M+H⁺).

Example 64

Using General Method F, Example A4 (100 mg, 0.332 mmol) and cyclohexylisocyanate (0.085 ml, 0.664 mmol) were reacted to afford1-cyclohexyl-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea(18 mg, 13% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.22(d, J=1.6 Hz, 1H), 8.08 (dd, J=2.0 and 6.8 Hz, 1H), 7.70 (s, 1H), 7.14(dd, J=8.8 and 11.2 Hz, 1H), 6.82-6.78 (m, 2H), 6.60-6.58 (m, 1H), 6.02(brs, 1H), 4.54 (s, 2H), 3.38 (brm, 1H), 3.14 (s, 3H), 2.76 (d, J=4.4Hz, 3H), 1.74-1.67 (m, 2H), 1.63-1.56 (m, 2H), 1.47-1.42 (m, 1H),1.27-1.08 (m, 5H); MS (ESI) m/z: 427.2 (M+H⁺).

Example 65

Using general method A, the TROC carbamate of Example B3 (75 mg, 0.238mmol) and Example A29 (80 mg, 0.233 mmol) were combined to provide1-(5-(1-tert-butyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butylisoxazol-5-yl)urea(50 mg, 41% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.35 (s, 1H), 8.77 (s,1H), 8.00 (dd, J=7.6, 2.4 Hz, 1H), 7.79 (s, 1H), 7.25 (m, 1H), 6.94 (m,1H), 6.40 (m, 1H), 6.35 (s, 1H), 6.07 (s, 1H), 4.38 (s, 2H), 2.75 (d,J=4.8 Hz, 1H), 1.57 (s, 9H), 1.23 (s, 9 H); MS (ESI) m/z: 510.2 (M+H⁺).

Example 66

Using general method F, 1-isocyanato-3-(trifluoromethyl)benzene (0.050g, 0.267 mmol) was reacted with Example A20 (0.093 g, 0.267 mmol) inmethylene chloride to provide1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea,(0.022 g, 15% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 11.85 (s, 1H), 8.27(s, 1H), 8.12 (s, 1H), 7.86 (d, J=7.5 Hz, 1H), 7.60 (t, J=8.5 Hz, 1H),7.43 (d, J=8 Hz, 1H), 7.37 (d, J=11 Hz, 1H), 6.94 (m, 2H), 5.58 (s, 2H),4.82 (d, J=14 Hz, 1H), 4.68 (d, J=14 Hz, 1H), 4.00 (q, J=6 Hz, 2H), 3.51(s, 3H), 1.24 (t, J=6 Hz, 3H); MS (ESI) m/z: 537.0 (M+H⁺).

Example 67

Using general method F, 1-isocyanato-3-(trifluoromethyl)benzene (0.05 g,0.267 mmol) was reacted with Example A20 (0.093 g, 0.266 mmol) in methylt-butyl ether (2 ml) for 2 hours to provide1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea(0.025 g, 17% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.46 (s, 1H), 8.56(s, 1H), 8.26 (d, J=8 Hz, 1H), 8.04 (s, 1H), 7.72 (s, 1H), 7.61 (d,J=10.5 Hz, 1H), 7.49 (m, 2H), 7.32 (m, 1H), 6.40 (m, 1H), 6.02 (s, 1H),4.61 (d, J=14 Hz, 1H), 4.40 (d, J=14 Hz, 1H), 3.77 (m, 2H), 2.75 (d,J=55 Hz, 3H), 1.15 (t, J=6 Hz, 3H); MS (ESI) m/z: 537.0 (M+H⁺).

Example 68

Using general method D, 2,3-difluorobenzoic acid (0.068 g, 0.430 mmol)and Example A20 (0.100 g, 0.287 mmol) were stirred at RT for one hourfollowed by heating at 80° C. for one more hour in dioxane (5 ml) toprovide1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea(0.015 g, 10% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.26 (brs, 1H), 8.31(d, J=9 Hz, 1H), 7.96 (m, 1H), 7.74 (s, 1H), 7.65 (d, J=11 Hz, 1H),7.17-7.0 (m, 2H), 6.47 (brs, 1H), 6.04 (s, 1H), 4.61 (d, J=13 Hz, 1H),4.43 (d, J=13 Hz, 1H), 3.81 (m, 2H), 2.76 (d, J=5 Hz, 3H), 1.17 (t, J=6Hz, 3H); MS (ESI) m/z: 505.0 (M+H⁺).

Example 69

Using general method A, Example B1 and Example A3 are combined to yield1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea.

Example 70

Using general method A and the same procedure as for Example A2, ExampleB5 and Example A3 are combined to yield1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea.

Example 71

Using general method A, Example B1 and Example A30 are combined to yield1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)urea.

Example 72

Using general method A, Example B5 and Example A30 are combined to yield1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)urea.

Example 73

Using general method A, Example B1 and Example A4 are combined to yield1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea.

Example 74

Using general method A, Example B5 and Example A4 are combined to yield1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea.

Example 75

Using general method A, Example B1 and Example A31 are combined to yield2-amino-6-(5-(3-tert-butyl-1-phenyl-1H-pyrazol-5-ylamino)-4-fluoro-2-methylphenyl)-8-methylpteridin-7(8H)-one.

Example 76

Using general method A, Example B5 and Example A31 are combined to yield2-amino-6-(5-(3-tert-butyl-1-methyl-1H-pyrazol-5-ylamino)-4-fluoro-2-methylphenyl)-8-methylpteridin-7(8H)-one.

Example 77

Using general method A, Example B11 and Example A5 are combined to yield1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropteridin-6-yl)phenyl)urea.

Example 78

Using general method A, Example A30 and Example B1 are combined to yield1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)urea.

Example 79

Using general method A, Example B1 and Example A4 are combined to yield1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)ureais synthesized.

The following examples are prepared by the methods described in Schemes1-12, General Methods A-G, the above Examples and the methods describedin WO 2006/071940.

Ex 801-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea811-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea821-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea831-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea84 1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2,4-difluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea85 1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2,4-difluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea861-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea871-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea881-(3-tert-butyl-4-chloroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea891-(3-tert-butyl-4-chloroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea901-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea 911-(3-tert-butyl-4-chloroisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea 921-(1-tert-butyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea93 1-(1-tert-butyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea94 1-(1-tert-butyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea95 1-(1-tert-butyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea961-(1-tert-butyl-1H-imidazol-4-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea 971-(1-tert-butyl-1H-imidazol-4-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea 981-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea991-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea1001-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea1011-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea1021-(1-tert-butyl-2-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea1031-(1-tert-butyl-2-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea104 1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea 1051-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea 1061-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea 1071-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea 1081-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-pyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea1091-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea 1101-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea 1111-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea1121-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea 1131-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea 1141-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea1151-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea1161-(4-tert-butylthiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea 1171-(4-tert-butyl-3-methylthiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea1181-(4-tert-butyl-3-chlorothiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea1191-(4-tert-butyl-3-fluorothiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea1201-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea1211-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea1221-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-tert-butylisoxazol-5-yl)urea 1231-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butylisoxazol-5-yl)urea 1241-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea 1251-(3-tert-butylisoxazol-5-yl)-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea 1261-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea 1271-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea 1281-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea 1291-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea 1301-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2,4-difluorophenyl)urea 1311-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea 1321-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2,4-difluorophenyl)urea 1331-(3-tert-butylisoxazol-5-yl)-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea 1341-(3-tert-butylisoxazol-5-yl)-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea 1351-(3-tert-butylisoxazol-5-yl)-3-(2,4-difluoro-5-(7-(methylamino)-2-oxo-1-phenyl-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea 1361-(3-tert-butylisoxazol-5-yl)-3-(2,4-difluoro-5-(7-(methylamino)-2-oxo-1-phenyl-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea 1371-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea 1381-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea 1391-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-isopropylisoxazol-5-yl)urea 1401-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-isopropylisoxazol-5-yl)urea 1411-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea1421-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea 1431-(1-tert-butyl-2-methyl-1H-pyrrol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea1441-(1-tert-butyl-2-methyl-1H-pyrrol-3-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea1451-(4-tert-butylfuran-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea 1461-(2-tert-butyloxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea 1471-cyclohexyl-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea 1481-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-((1R,2R)-2-methylcyclohexyl)urea 1491-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-((1S,2S)-2-methylcyclohexyl)urea 1501-cyclohexyl-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea 1511-(bicyclo[2.2.1]heptan-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea 1521-(bicyclo[2.2.1]hept-5-en-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea1531-cyclopropyl-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea 1541-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-isopropylurea 1551-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-(pyridin-3-yl)ethyl)urea 156(R)-1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenylethyl)urea 157(S)-1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenylethyl)urea 1581-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea 1591-cyclohexyl-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea 1601-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea1611-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea 1621-cyclohexyl-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea1631-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea 1641-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(tetrahydrofuran-3-yl)-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea1651-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(pyrrolidin-3-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea 1661-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(piperidin-4-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea1671-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(tetrahydrofuran-3-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea1681-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea 1691-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(3-hydroxycyclopentyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea1701-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(3-fluorophenyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea 1711-(2-fluoro-5-(1-(3-fluorophenyl)-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropylisoxazol-5-yl)urea 1721-(3-tert-butylisoxazol-5-yl)-3-(5-(7-(1,3-dimethyl-1H-pyrazol-5-ylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea173 1-(3-(7-(1,3-dimethyl-1H-pyrazol-5-ylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea 1741-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea

B-Raf(V600E) Kinase Assay: The activity of B-Raf(V600E) kinase wasdetermined by following the formation of ADP from the reaction throughcoupling with the pyruvate kinase/lactate dehydrogenase system (e.g.,Schindler, et al. Science (2000) 289, 1938-1942). In this assay, theoxidation of NADH (thus the decrease at A_(340nm)) was continuouslymonitored spectrophotometrically. The reaction mixture (100 μl)contained B-Raf(V600E) kinase (2.1 nM nominal concentration),unphosphorylated, full-length MEK1 (45 nM), MgCl₂ (13 mM), pyruvatekinase (3.5 units), lactate dehydrogenase (5.5 units),phosphoenolpyruvate (1 mM), and NADH (0.28 mM), in 60 mM Tris buffer,containing 0.13% octyl-glucoside and 3.5% DMSO concentration at pH 7.5.The test compounds were incubated with the reaction mixture at 30° C.for 2 h or 4 h. The reaction was initiated by adding ATP (0.2 mM, finalconcentration). The absorption at 340 nm was continuously monitored for3 h at 30° C. on a Polarstar Optima plate reader (BMG). The reactionrate was calculated using the 1.5 h to 2.5 h time frame. Percentinhibition was obtained by comparison of reaction rate with that of acontrol (i.e. with no test compound). IC₅₀ values were calculated from aseries of percent inhibition values determined at a range of inhibitorconcentrations using software routines as implemented in the GraphPadPrism software package.

B-Raf(V600E) protein sequence used for screening: (SEQ. ID NO. 1)EDRNRMKTLGRRDSSDDWEIPDGQITVGQRIGSGSFGTVYKGKWHGDVAVKMLNVTAPTPQQLQAFKNEVGVLRKTRHVNILLFMGYSTKPQLAIVTQWCEGSSLYHHLHIIETKFEMIKLIDIARQTAQGMDYLHAKSIIHRDLKSNNIFLHEDLTVKIGDFGLATEKSRWSGSHQFEQLSGSILWMAPEVIRMQDKNPYSFQSDVYAFGIVLYELMTGQLPYSNINNRDQIIFMVGRGYLSPDLSKVRSNCPKAMKRLMAECLKKKRDERPLFPQILASIELLARSLPKIHRMEK1 protein sequence used for screening: (SEQ. ID NO. 2)MELKDDDFEKISELGAGNGGVVFKVSHKPSGLVMARKLIHLEIKPAIRNQIIRELQVLHECNSPYIVGFYGAFYSDGEISICMEHMDGGSLDQVLKKAGRIPEQILGKVSIAVIKGLTYLREKHKIMHRDVKPSNILVNSRGEIKLCDFGVSGQLIDSMANSFVGTRSYMSPERLQGTHYSVQSDIWSMGLSLVEMAVGRYPIPPPDAKELELMFGCQVEGDAAETPPRPRTPGRPLSSYGMDSRPPMAIFELLDYIVNEPPPKLPSGVFSLEFQDFVNKCLIKNPAERADLKQLMVHAFIKRSDAEEVDFAGWLCSTIGLNQPSTPTHAAGV

C-Raf Kinase Assay: The activity of C-Raf kinase was determined byfollowing the formation of ADP from the reaction through coupling withthe pyruvate kinase/lactate dehydrogenase system (e.g., Schindler, etal. Science (2000) 289, 1938-1942). In this assay, the oxidation of NADH(thus the decrease at A_(340nm)) was continuously monitoredspectrophotometrically. The reaction mixture (100 μl) contained C-Rafkinase (0.28 nM nominal concentration, available from Upstate, catalogue#14-352), unphosphorylated, full-length MEK1 (27 nM), MgCl₂ (13 mM),pyruvate kinase (3.5 units), lactate dehydrogenase (5.5 units),phosphoenolpyruvate (1 mM), and NADH (0.28 mM), in 60 mM Tris buffer,containing 0.13% octyl-glucoside and 3.5% DMSO concentration at pH 7.5.The test compounds were incubated with the reaction mixture at 30° C.for 2 h or 4 h. The reaction was initiated by adding ATP (0.2 mM, finalconcentration). The absorption at 340 nm was continuously monitored for3 h at 30° C. on a Polarstar Optima plate reader (BMG). The reactionrate was calculated using the 1.0 h to 2.0 h time frame. Percentinhibition was obtained by comparison of reaction rate with that of acontrol (i.e. with no test compound). IC₅₀ values were calculated from aseries of percent inhibition values determined at a range of inhibitorconcentrations using software routines as implemented in the GraphPadPrism software package.

In general, compounds 1-68 disclosed herein exhibited >50% inhibitionactivity at 0.2-2 uM concentration against V600E BRaf and CRaf kinasesutilizing the above assay conditions.

Cell Culture: A-375 cells were obtained from American Type CultureCollection (Rockville, Md.). Briefly, cells were grown in Dulbecco'sModified Eagle Medium with 4.5 g/L glucose, 6 mM L-glutamine, and 10%certified fetal bovine serum (Invitrogen, Carlsbad, Calif.) at 37degrees Celsius, 5% CO2, 95% humidity. Cells were allowed to expanduntil reaching 80% confluency at which point they were subcultured orharvested for assay use.

Cell Proliferation Assay: A serial dilution of test compound wasdispensed into a 96 well black clear bottom plate (Corning, Corning,N.Y.). Five thousand cells (A375) were then added to each well in growthmedium. Plates were incubated for 72 hours at 37 degrees Celsius, 5%CO2, 95% humidity. At the end of the incubation period Cell Titer Blue(Promega, Madison, Wis.) was added to each well and an additional 4.5hour incubation at 37 degrees Celsius, 5% CO2, 95% humidity wasperformed. Plates were then read on a BMG Fluostar Optima (BMG, Durham,N.C.) using an excitation of 544 nM and an emission of 612 nM. Data wasanalyzed using Prism software (Graphpad, San Diego, Calif.) to calculateIC₅₀ values.

In general, compounds 1-68 disclosed herein exhibited >50% inhibition ofproliferation at 1-10 uM concentration against A375 cells utilizing theabove assay conditions.

All references mentioned or referred to herein are incorporated byreference into this disclosure.

1-98. (canceled)
 99. A method of modulating a kinase activity of awild-type kinase species, oncogenic forms thereof, aberrant fusionproteins thereof and polymorphs of any of the foregoing, comprising thestep of contacting said species with a compound of the formula Ia′ orIIa′

wherein X—Y is N—CH2; X2 is a direct bond; E1 is phenyl; Q1 is N and Q2is CR3; A is selected from the group consisting of phenyl, naphthyl,C3-C8carbocyclyl, bicycloheptanyl, bicycloheptenyl, and G1; G1 is aheteroaryl taken from the group consisting of pyrrolyl, furyl, thienyl,oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl,oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl,pyridazinyl, triazinyl, pyridinyl, and pyrimidinyl; the A ring may beoptionally substituted with one or more —X1-A1 moieties; X1 is selectedfrom the group consisting of —(CH₂)_(n)—(O)_(r)—(CH₂)_(n)—,—(CH₂)_(n)—(NR3)-(CH₂)_(n)—, —(CH₂)_(n)—(S)_(r)—(CH₂)_(n)—,—(CH₂)_(n)—(C═O)_(r)—(CH₂)_(n)—, —(CH₂)_(n)—(C(═O)—NR3)_(r)-(CH₂)_(n)—,and —(CH₂)_(n)—(SO₂—NR3)_(r)-(CH₂)_(n)—, wherein any of the alkylenesmay be straight or branched chain; A1 is selected from the groupconsisting of hydrogen, aryl, G1, C1-C6 alkyl, branched C3-C8alkyl, R19substituted C3-C8carbocyclyl, fluoroC1-C6alkyl wherein the alkyl isfully or partially fluorinated, halogen, cyano, hydroxyl, —N(R4)₂, —R5,—C(O)N(R4)₂, C(O)R5, C1-C6alkoxy, and fluoroC1-C6alkoxy wherein thealkyl group is fully or partially fluorinated; when A and A1 have one ormore substitutable sp2-hybridized carbon atom, each respective sp2hybridized carbon atom may be optionally substituted with a Z1 or Z3substituent; when A and A1 have one or more substitutable sp3-hybridizedcarbon atom, each respective sp3 hybridized carbon atom may beoptionally substituted with a Z2 or R3 substituent; when A and A1 haveone or more substitutable nitrogen atom, each respective nitrogen atommay be optionally substituted with a Z4 substituent; each Z1 isindependently and individually selected from the group consisting ofhydrogen, hydroxyC1-C6alkyl, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl,(R4)₂NC1-C6alkyl, (R4)₂NC2-C6alkylN(R4)-(CH₂)_(n),(R4)₂NC2-C6alkylO—(CH₂)_(n), (R3)₂N—C(═O)—, (R4)₂N—C(═O)—,(R4)₂N—CO—C1-C6alkyl-, C1-C6alkoxycarbonyl-, -carboxyC1-C6alkyl,C1-C6alkoxycarbonylC1-C6alkyl, (R3)₂NSO₂—, —SOR3, (R4)₂NSO₂—, —SO₂R3,—SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, —(CH₂)_(n)N(R4)C(O)R8,—(CH₂)_(n)-G1, —(CH₂)_(n)-G4, phenoxy, —(CH₂)_(n)—O—(CH₂)_(n)-G1,—(CH₂)_(n)—O—(CH₂)_(n)-G4, —(CH₂)_(n)—NR3-(CH₂)_(n)-aryl,—(CH₂)_(n)—NR3-(CH₂)_(n)-G1, —(CH₂)_(n)—NR3-(CH₂)_(n)-G4, —S(O)₂R5,—N═S(O)R6R8, —S(O)(═NR3)R6, —(CH₂)_(n)NHC(O)NHS(O)₂R8,—(CH₂)_(n)NHS(O)₂NHC(O)R8, —C(O)NHS(O)₂R8, —S(O)₂NHC(O)R8,—(CH₂)_(n)NHC(O)(CH₂)_(n)R5, —(CH₂)_(n)NHS(O)₂ (CH₂)_(n)R5,—(CH₂)_(n)C(O)NH(CH₂)_(q)R5, —(CH₂)_(n)C(O)R5, —(CH₂)_(n)OC(O)R5,—(CH₂)_(n)S(O)₂NH(CH₂)_(q)R5, —CH(OH)(CH₂)_(p)R5, —CH(OH)CH(OH)R4,—(CH₂)_(n)N(R4)₂, —(CH₂)_(n)R5, —C(═NH)R5, —C(═NH)N(R4)₂, —C(═NOR3)R5,—C(═NOR3)N(R4)₂, and —NHC(═NH)R8; in the event that Z1 contains an alkylor alkylene moiety, such moieties may be further substituted with one ormore C1-C6alkyls; each Z2 is independently and individually selectedfrom the group consisting of hydrogen, aryl, C1-C6alkyl,C3-C8carbocyclyl, hydroxyl, hydroxyC1-C6alkyl-, cyano, (R3)₂N—, (R4)₂N—,(R4)₂NC1-C6alkyl-, (R4)₂NC2-C6alkylN(R4)-(CH₂)_(n)—,(R4)₂NC2-C6alkylO—(CH₂)_(n)—, (R3)₂N—C(═O)—, (R4)₂N—C(═O)—,(R4)₂N—CO—C1-C6alkyl-, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl,C1-C6alkoxycarbonylC1-C6alkyl, (R3)₂NSO₂—, (R4)₂NSO₂—, —SO₂R5, —SO₂R8,—(CH₂)_(n)N(R4)C(O)R8, —C(O)R8, ═O═NOH, ═N(OR6), —(CH₂)_(n)-G1,—(CH₂)_(n)-G4, —(CH₂)_(n)—O—(CH₂)_(n)-G1, —(CH₂)_(n)—O—(CH₂)_(n)-G4,—(CH₂)_(n)—NR3-(CH₂)_(n)-aryl, —(CH₂)_(n)—NR3-(CH₂)_(n)-G1,—(CH₂)_(n)—NR3-(CH₂)_(n)-G4, —(CH₂)_(n)NHC(O)NHS(O)₂R8,—(CH₂)_(n)NHS(O)₂NHC(O)R8, —C(O)NHS(O)₂R8, —(CH₂)NHC(O)(CH₂)_(n)R5,—(CH₂)_(n)NHS(O)₂R5, —(CH₂)_(n)C(O)NH(CH₂)_(q)R5, —(CH₂)_(n)C(O)R5,—(CH₂)_(n)OC(O)R5, and —(CH₂)_(n)R5; in the event that Z2 contains analkyl or alkylene moiety, such moieties may be further substituted withone or more C1-C6alkyls; each Z3 is independently and individuallyselected from the group consisting of H, C1-C6alkyl, branchedC3-C7alkyl, C3-C8carbocyclyl, halogen, fluoroalkyl wherein the alkylmoiety can be partially or fully fluorinated, cyano, hydroxyl, methoxy,oxo, (R3)₂N—C(═O)—, (R4)₂N—C(═O)—, —N(R4)-C(═O)R8, (R3)₂NSO₂—,(R4)₂NSO₂—, —N(R4)SO₂R5, —N(R4)SO₂R8, —(CH₂)_(n)—N(R3)₂,—(CH₂)_(n)—N(R4)₂, —O—(CH₂)_(q)—N(R4)₂, —O—(CH₂)_(q)—O-alkyl,—N(R3)-(CH₂)_(q)—O-alkyl, —N(R3)-(CH₂)_(q)—N(R4)₂, —O—(CH₂)_(q)—R5,—N(R3)-(CH₂)_(q)—R5, —C(═O)R5, —C(═O)R8, and nitro; in the event that Z3contains an alkyl or alkylene moiety, such moieties may be furthersubstituted with one or more C1-C6alkyls; each Z4 is independently andindividually selected from the group consisting of H, C1-C6alkyl,hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4)₂N—C2-C6alkyl,(R4)₂N—C2-C6alkylN(R4)-C2-C6alkyl, (R4)₂N—C2-C6alkyl-O—C2-C6alkyl,(R4)₂N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl,—C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO₂R8, —COR8, —(CH₂)_(n)-G1,—(CH₂)_(n)-G4, —(CH₂)_(q)—O—(CH₂)_(n)-G1, —(CH₂)_(q)—O—(CH₂)_(n)-G4,—(CH₂)_(q)—NR3-(CH₂)_(n)-G1, —(CH₂)_(q)—NR3-(CH₂)_(n)-G4,—(CH₂)_(q)NHC(O)(CH₂)_(n)R5, —(CH₂)_(q)C(O)NH(CH₂)_(q)R5,—(CH₂)_(q)C(O)R5, —(CH₂)_(q)OC(O)R5, —(CH₂)_(q)R5,—(CH₂)_(q)NR4(CH₂)_(q)R5, and —(CH₂)_(q)O(CH₂)_(q)R5; in the event thatZ4 contains an alkyl or alkylene moiety, such moieties may be furthersubstituted with one or more C1-C6alkyls; each Z6 is independently andindividually selected from the group consisting of H, C1-C6alkyl,branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, —OR4, C1-C6alkylthio,(R3)₂N—, (R4)₂N—, —R5, —N(R3)COR8, —N(R4)COR8, —N(R3)SO₂R6-, —CON(R3)₂,—CON(R4)₂, —COR5, —SO₂N(R4)₂, halogen, fluoroC1-C6alkyl wherein thealkyl is fully or partially fluorinated, cyano, fluoroC1-C6alkoxywherein the alkyl is fully or partially fluorinated,—O—(CH₂)_(q)—N(R4)₂, —N(R3)-(CH₂)_(q)—N(R4)₂, —O—(CH₂)_(q)—O-alkyl,—N(R3)-(CH₂)_(q)—O-alkyl, —O—(CH₂)_(q)—R5, —N(R3)-(CH₂)_(q)—R5,—(NR3)_(r)-(CH₂)_(n)—R17, —(O)_(r)—R17, —(S)_(r)—R17, and—(CH₂)_(r)—R17; in the event that Z6 contains an alkyl or alkylenemoiety, such moieties may be further substituted with one or moreC1-C6alkyls; wherein each R3 is independently and individually selectedfrom the group consisting of H, C1-C6alkyl, branched C3-C7alkyl,C3-C8carbocyclyl, and Z3-substituted phenyl; each R4 is independentlyand individually selected from the group consisting of H, C1-C6alkyl,hydroxyC1-C6alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branchedC3-C7alkyl, branched hydroxyC1-C6alkyl, branched C1-C6alkoxyC1-C6alkyl,branched dihydroxyC1-C6alkyl, —(CH₂)—N(R7)₂, —(CH₂)—R5,—(CH₂)—C(O)N(R7)₂, —(CH₂)_(n)C(O)R5, —(CH₂)_(n)—C(O)OR3,C3-C8carbocyclyl, hydroxyl substituted C3-C8carbocyclyl, alkoxysubstituted C3-C8carbocyclyl, dihydroxy substituted C3-C8carbocyclyl,and —(CH₂)_(n)—R17; each R5 is independently and individually selectedfrom the group consisting of

and wherein the symbol (##) is the point of attachment of the R5 moiety;each R6 is independently and individually selected from the groupconsisting of C1-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, phenyl,and G1; each R7 is independently and individually selected from thegroup consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl,dihydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, branched C3-C7alkyl,branched hydroxyC2-C6 alkyl, branched C1-C6alkoxyC2-C6alkyl, brancheddihydroxyC2-C6alkyl, —(CH₂)_(q)—R5, —(CH₂)_(n)—C(O)R5,—(CH₂)_(n)—C(O)OR3, C3-C8carbocyclyl, hydroxyl substitutedC3-C8carbocyclyl, alkoxy substituted C3-C8carbocyclyl, dihydroxysubstituted C3-C8carbocyclyl, and —(CH₂)_(n)—R17; each R8 isindependently and individually selected from the group consisting ofC1-C6alkyl, branched C3-C7alkyl, fluoroalkyl wherein the alkyl moiety ispartially or fully fluorinated, C3-C8carbocyclyl, Z3-substituted phenyl,Z3-substituted phenyl C1-C6alkyl, Z3-substituted G1, Z3-substitutedG1-C1-C6alkyl, OH, C1-C6alkoxy, N(R3)₂, N(R4)₂, and R5; each R10 isindependently and individually selected from the group consisting ofCO₂H, CO₂C1-C6alkyl, CO—N(R4)₂, OH, C1-C6alkoxy, and —N(R4)₂; R16 isindependently and individually selected from the group consisting ofhydrogen, C1-C6alkyl, and halogen; each R17 is taken from the groupcomprising phenyl, naphthyl, pyrrolyl, furyl, thienyl, oxazolyl,thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl,oxetanyl, azetadinyl, tetrahydrofuranyl, oxazolinyl, oxazolidinyl,pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, azepinyl, oxepinyl,diazepinyl, pyrrolidinyl, and piperidinyl; wherein R17 can be furthersubstituted with one or more Z2, Z3 or Z4 moieties; R19 is H or C1-C6alkyl; wherein two R3 or R4 moieties are independently and individuallytaken from the group consisting of C1-C6alkyl and branched C3-C6alkyl,hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogenatom, said moieties may cyclize to form a C3-C7 heterocyclyl ring; and kis 1 or 2; n is 0-6; p is 1-4; q is 2-6; r is 0 or 1; t is 1-3, andsalts thereof.
 100. The method of claim 99, said species being C-Rafkinase, B-Raf kinase and oncogenic forms thereof.
 101. The method ofclaim 99 wherein said compound is selected from the group consisting of1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-t-butyl-1-phenyl-1H-pyrazol-5-yl)urea,1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-t-butyl-1-methyl-1H-pyrazol-5-yl)urea,1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea,1-(3-tert-butylphenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea,1-(3-t-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea,1-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea,1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea,1-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(naphthalen-1-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea,1-(2-tert-butyl-4-(piperazin-1-yl)pyrimidin-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-cyclohexyl-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-cyclohexyl-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-cyclohexyl-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(1-tert-butyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butylisoxazol-5-yl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea,and salts thereof.
 102. The method of claim 99 wherein said compound isselected from the group consisting of1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)urea,1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)urea,1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2,4-difluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2,4-difluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-chloroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-chloroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-tert-butyl-4-chloroisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(1-tert-butyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-imidazol-4-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(1-tert-butyl-1H-imidazol-4-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-2-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-2-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-pyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea,1-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-tert-butylthiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-tert-butyl-3-methylthiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-tert-butyl-3-chlorothiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-tert-butyl-3-fluorothiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-tert-butylisoxazol-5-yl)urea,1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butylisoxazol-5-yl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2,4-difluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2,4-difluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2,4-difluoro-5-(7-(methylamino)-2-oxo-1-phenyl-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2,4-difluoro-5-(7-(methylamino)-2-oxo-1-phenyl-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(1-tert-butyl-2-methyl-1H-pyrrol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-2-methyl-1H-pyrrol-3-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-tert-butylfuran-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(2-tert-butyloxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-cyclohexyl-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-((1R,2R)-2-methylcyclohexyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-((1S,2S)-2-methylcyclohexyl)urea,1-cyclohexyl-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(bicyclo[2.2.1]heptan-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-cyclopropyl-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-cyclohexyl-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-cyclohexyl-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(tetrahydrofuran-3-yl)-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(pyrrolidin-3-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(piperidin-4-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(tetrahydrofuran-3-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(3-hydroxycyclopentyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(3-fluorophenyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(2-fluoro-5-(1-(3-fluorophenyl)-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(7-(1,3-dimethyl-1H-pyrazol-5-ylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-(7-(1,3-dimethyl-1H-pyrazol-5-ylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,and salts thereof.
 103. The method of claim 99 wherein said compound isselected from the group consisting of1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(naphthalen-1-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea,and salts thereof.
 104. The method of claim 99 wherein said compound isselected from the group consisting of1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,and salts thereof.
 105. The method of claims 101-104, said species beingC-Raf kinase, B-Raf kinase and oncogenic forms thereof.
 106. A method oftreating an individual suffering from a condition selected from thegroup consisting of cancer, hyperproliferative diseases, secondarycancer growth arising from metastasis, diseases characterized byhyper-vascularization, inflammation, osteoarthritis, respiratorydiseases, stroke, systemic shock, immunological diseases, cardiovasculardisease and diseases characterized by angiogenesis, comprising the stepof administering to such individual a compound of the formula Ia′ orIIa′

wherein X—Y is N—CH₂; X2 is a direct bond; E1 is phenyl; Q1 is N and Q2is CR3; A is selected from the group consisting of phenyl, naphthyl,C3-C8carbocyclyl, bicycloheptanyl, bicycloheptenyl, and G1; G1 is aheteroaryl taken from the group consisting of pyrrolyl, furyl, thienyl,oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl,oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl,pyridazinyl, triazinyl, pyridinyl, and pyrimidinyl; the A ring may beoptionally substituted with one or more —X1-A1 moieties; X1 is selectedfrom the group consisting of —(CH₂)_(n)—(O), —(CH₂)_(n)—,—(CH₂)_(n)—(NR3)_(r)-(CH₂)_(n)—, —(CH₂)_(n)—(S)_(r)—(CH₂)_(n)—,—(CH₂)_(n)—(C═O)_(r)—(CH₂)_(n)—, —(CH₂)_(n)—(C(═O)—NR3)_(r)-(CH₂)_(n)—,and —(CH₂)_(n)—(SO₂—NR3)_(r)-(CH₂)_(n)—, wherein any of the alkylenesmay be straight or branched chain; A1 is selected from the groupconsisting of hydrogen, aryl, G1, C1-C6 alkyl, branched C3-C8alkyl, R19substituted C3-C8carbocyclyl, fluoroC1-C6alkyl wherein the alkyl isfully or partially fluorinated, halogen, cyano, hydroxyl, —N(R4)₂, —R5,—C(O)N(R4)₂, C(O)R5, C1-C6alkoxy, and fluoroC1-C6alkoxy wherein thealkyl group is fully or partially fluorinated; when A and A1 have one ormore substitutable sp2-hybridized carbon atom, each respective sp2hybridized carbon atom may be optionally substituted with a Z1 or Z3substituent; when A and A1 have one or more substitutable sp3-hybridizedcarbon atom, each respective sp3 hybridized carbon atom may beoptionally substituted with a Z2 or R3 substituent; when A and A1 haveone or more substitutable nitrogen atom, each respective nitrogen atommay be optionally substituted with a Z4 substituent; each Z1 isindependently and individually selected from the group consisting ofhydrogen, hydroxyC1-C6alkyl, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl,(R4)₂NC1-C6alkyl, (R4)₂NC2-C6alkylN(R4)-(CH₂)_(n),(R4)₂NC2-C6alkylO—(CH₂)_(n), (R3)₂N—C(═O)—, (R4)₂N—C(═O)—,(R4)₂N—CO—C1-C6alkyl-, C1-C6alkoxycarbonyl-, -carboxyC1-C6alkyl,C1-C6alkoxycarbonylC1-C6alkyl, (R3)₂NSO₂—, —SOR3, (R4)₂NSO₂—, —SO₂R3,—SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, —(CH₂)_(n)N(R4)C(O)R8,—(CH₂)_(n)-G1, —(CH₂)_(n)-G4, phenoxy, —(CH₂)_(n)—O—(CH₂)_(n)-G1,—(CH₂)_(n)—O—(CH₂)_(n)-G4, —(CH₂)_(n)—NR3-(CH₂)_(n)-aryl,—(CH₂)_(n)—NR3-(CH₂)_(n)-G1, —(CH₂)_(n)—NR3-(CH₂)_(n)-G4, —S(O)₂R5,—N═S(O)R6R8, —S(O)(═NR3)R6, —(CH₂)_(n)NHC(O)NHS(O)₂R8,—(CH₂)_(n)NHS(O)₂NHC(O)R8, —C(O)NHS(O)₂R8, —S(O)₂NHC(O)R8,—(CH₂)_(n)NHC(O)(CH₂)_(n)R5, —(CH₂)_(n)NHS(O)₂ (CH₂)_(n)R5,—(CH₂)_(n)C(O)NH(CH₂)_(q)R5, —(CH₂)_(n)C(O)R5, —(CH₂)_(n)OC(O)R5,—(CH₂)_(n)S(O)₂NH(CH₂)_(q)R5, —CH(OH)(CH₂)_(p)R5, —CH(OH)CH(OH)R4,—(CH₂)_(n)N(R4)₂, —(CH₂)_(n)R5, —C(═NH)R5, —C(═NH)N(R4)₂, —C(═NOR3)R5,—C(═NOR3)N(R4)₂, and —NHC(═NH)R8; in the event that Z1 contains an alkylor alkylene moiety, such moieties may be further substituted with one ormore C1-C6alkyls; each Z2 is independently and individually selectedfrom the group consisting of hydrogen, aryl, C1-C6alkyl,C3-C8carbocyclyl, hydroxyl, hydroxyC1-C6alkyl-, cyano, (R3)₂N—, (R4)₂N—,(R4)₂NC1-C6alkyl-, (R4)₂NC2-C6alkylN(R4)-(CH₂)_(n)—,(R4)₂NC2-C6alkylO—(CH₂)_(n)—, (R3)₂N—C(═O)—, (R4)₂N—C(═O)—,(R4)₂N—CO—C1-C6alkyl-, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl,C1-C6alkoxycarbonylC1-C6alkyl, (R3)₂NSO₂—, (R4)₂NSO₂—, —SO₂R5, —SO₂R8,—(CH₂)_(n)N(R4)C(O)R8, —C(O)R8, ═O, ═NOH, ═N(OR6), —(CH₂)_(n)-G1,—(CH₂)_(n)-G4, —(CH₂)_(n)—O—(CH₂)_(n)-G1, —(CH₂)_(n)—O—(CH₂)_(n)-G4,—(CH₂)_(n)—NR3-(CH₂)_(n)-aryl, —(CH₂)_(n)—NR3-(CH₂)_(n)-G1,—(CH₂)_(n)—NR3-(CH₂)_(n)-G4, —(CH₂)_(n)NHC(O)NHS(O)₂R8,—(CH₂)_(n)NHS(O)₂NHC(O)R8, —C(O)NHS(O)₂R8, —(CH₂)NHC(O)(CH₂)_(n)R5,—(CH₂)_(n)NHS(O)₂R5, —(CH₂)_(n)C(O)NH(CH₂)_(q)R5, —(CH₂)_(n)C(O)R5,—(CH₂)_(n)OC(O)R5, and —(CH₂)_(n)R5; in the event that Z2 contains analkyl or alkylene moiety, such moieties may be further substituted withone or more C1-C6alkyls; each Z3 is independently and individuallyselected from the group consisting of H, C1-C6alkyl, branchedC3-C7alkyl, C3-C8carbocyclyl, halogen, fluoroalkyl wherein the alkylmoiety can be partially or fully fluorinated, cyano, hydroxyl, methoxy,oxo, (R3)₂N—C(═O)—, (R4)₂N—C(═O)—, —N(R4)-C(═O)R8, (R3)₂NSO₂—,(R4)₂NSO₂—, —N(R4)SO₂R5, —N(R4)SO₂R8, —(CH₂)_(n)—N(R3)₂,—(CH₂)_(n)—N(R4)₂, —O—(CH₂)_(q)—N(R4)₂, —O—(CH₂)_(q)—O-alkyl,—N(R3)-(CH₂)_(q)—O-alkyl, —N(R3)-(CH₂)_(q)—N(R4)₂, —O—(CH₂)_(q)—R5,—N(R3)-(CH₂)_(q)—R5, —C(═O)R5, —C(═O)R8, and nitro; in the event that Z3contains an alkyl or alkylene moiety, such moieties may be furthersubstituted with one or more C1-C6alkyls; each Z4 is independently andindividually selected from the group consisting of H, C1-C6alkyl,hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4)₂N—C2-C6alkyl,(R4)₂N—C2-C6alkylN(R4)-C2-C6alkyl, (R4)₂N—C2-C6alkyl-O—C2-C6alkyl,(R4)₂N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl,—C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO₂R8, —COR8, —(CH₂)_(n)-G1,—(CH₂)_(n)-G4, —(CH₂)_(q)—O—(CH₂)_(n)-G1, —(CH₂)_(q)—O—(CH₂)_(n)-G4,—(CH₂)_(q)—NR3-(CH₂)_(n)-G1, —(CH₂)_(q)—NR3-(CH₂)_(n)-G4,—(CH₂)_(q)NHC(O)(CH₂)_(n)R5, —(CH₂)_(q)C(O)NH(CH₂)_(q)R5,—(CH₂)_(q)C(O)R5, —(CH₂)_(q)OC(O)R5, —(CH₂)_(q)R5,—(CH₂)_(q)NR4(CH₂)_(q)R5, and —(CH₂)_(q)O(CH₂)_(q)R5; in the event thatZ4 contains an alkyl or alkylene moiety, such moieties may be furthersubstituted with one or more C1-C6alkyls; each Z6 is independently andindividually selected from the group consisting of H, C1-C6alkyl,branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, —OR4, C1-C6alkylthio,(R3)₂N—, (R4)₂N—, —R5, —N(R3)COR8, —N(R4)COR8, —N(R3)SO₂R6-, —CON(R3)₂,—CON(R4)₂, —COR5, —SO₂N(R4)₂, halogen, fluoroC1-C6alkyl wherein thealkyl is fully or partially fluorinated, cyano, fluoroC1-C6alkoxywherein the alkyl is fully or partially fluorinated,—O—(CH₂)_(q)—N(R4)₂, —N(R3)-(CH₂)_(q)—N(R4)₂, —O—(CH₂)_(q)—O-alkyl,—N(R3)-(CH₂)_(q)—O-alkyl, —O—(CH₂)_(q)—R5, —N(R3)-(CH₂)_(q)—R5,—(NR3)_(r)-(CH₂)_(n)—R17, —(O)_(r)—R17, —(S)_(r)—R17, and—(CH₂)_(r)—R17; in the event that Z6 contains an alkyl or alkylenemoiety, such moieties may be further substituted with one or moreC1-C6alkyls; wherein each R3 is independently and individually selectedfrom the group consisting of H, C1-C6alkyl, branched C3-C7alkyl,C3-C8carbocyclyl, and Z3-substituted phenyl; each R4 is independentlyand individually selected from the group consisting of H, C1-C6alkyl,hydroxyC1-C6alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branchedC3-C7alkyl, branched hydroxyC1-C6alkyl, branched C1-C6alkoxyC1-C6alkyl,branched dihydroxyC1-C6alkyl, —(CH₂)_(p)—N(R7)₂, —(CH₂)_(p)—R5,—(CH₂)_(p)—C(O)N(R7)₂, —(CH₂)_(n)C(O)R5, —(CH₂)_(n)—C(O)OR3,C3-C8carbocyclyl, hydroxyl substituted C3-C8carbocyclyl, alkoxysubstituted C3-C8carbocyclyl, dihydroxy substituted C3-C8carbocyclyl,and —(CH₂)_(n)—R17; each R5 is independently and individually selectedfrom the group consisting of

and wherein the symbol (##) is the point of attachment of the R5 moiety;each R6 is independently and individually selected from the groupconsisting of C1-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, phenyl,and G1; each R7 is independently and individually selected from thegroup consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl,dihydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, branched C3-C7alkyl,branched hydroxyC2-C6 alkyl, branched C1-C6alkoxyC2-C6alkyl, brancheddihydroxyC2-C6alkyl, —(CH₂)_(q)—R5, —(CH₂)_(n)—C(O)R5,—(CH₂)_(n)—C(O)OR3, C3-C8carbocyclyl, hydroxyl substitutedC3-C8carbocyclyl, alkoxy substituted C3-C8carbocyclyl, dihydroxysubstituted C3-C8carbocyclyl, and —(CH₂)_(n)—R17; each R8 isindependently and individually selected from the group consisting ofC1-C6alkyl, branched C3-C7alkyl, fluoroalkyl wherein the alkyl moiety ispartially or fully fluorinated, C3-C8carbocyclyl, Z3-substituted phenyl,Z3-substituted phenyl C1-C6alkyl, Z3-substituted G1, Z3-substitutedG1-C1-C6alkyl, OH, C1-C6alkoxy, N(R3)₂, N(R4)₂, and R5; each R10 isindependently and individually selected from the group consisting ofCO₂H, CO₂C1-C6alkyl, CO—N(R4)₂, OH, C1-C6alkoxy, and —N(R4)₂; R16 isindependently and individually selected from the group consisting ofhydrogen, C1-C6alkyl, and halogen; each R17 is taken from the groupcomprising phenyl, naphthyl, pyrrolyl, furyl, thienyl, oxazolyl,thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl,oxetanyl, azetadinyl, tetrahydrofuranyl, oxazolinyl, oxazolidinyl,pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, azepinyl, oxepinyl,diazepinyl, pyrrolidinyl, and piperidinyl; wherein R17 can be furthersubstituted with one or more Z2, Z3 or Z4 moieties; R19 is H or C1-C6alkyl; wherein two R3 or R4 moieties are independently and individuallytaken from the group consisting of C1-C6alkyl and branched C3-C6alkyl,hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogenatom, said moieties may cyclize to form a C3-C7 heterocyclyl ring; and kis 1 or 2; n is 0-6; p is 1-4; q is 2-6; r is 0 or 1; t is 1-3, andsalts thereof.
 107. The method of claim 106 wherein said compound isselected from the group consisting of1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-t-butyl-1-phenyl-1H-pyrazol-5-yl)urea,1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-t-butyl-1-methyl-1H-pyrazol-5-yl)urea,1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea,1-(3-tert-butylphenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea,1-(3-t-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea,1-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea,1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea,1-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(naphthalen-1-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea,1-(2-tert-butyl-4-(piperazin-1-yl)pyrimidin-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-cyclohexyl-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-cyclohexyl-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-cyclohexyl-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(1-tert-butyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butylisoxazol-5-yl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea,and salts thereof.
 108. The method of claim 106 wherein said compound isselected from the group consisting of1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)urea,1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)urea,1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2,4-difluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2,4-difluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-chloroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-chloroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-tert-butyl-4-chloroisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(1-tert-butyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-imidazol-4-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(1-tert-butyl-1H-imidazol-4-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-2-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-2-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-pyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea,1-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-tert-butylthiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-tert-butyl-3-methylthiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-tert-butyl-3-chlorothiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-tert-butyl-3-fluorothiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-tert-butylisoxazol-5-yl)urea,1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butylisoxazol-5-yl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2,4-difluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2,4-difluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2,4-difluoro-5-(7-(methylamino)-2-oxo-1-phenyl-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2,4-difluoro-5-(7-(methylamino)-2-oxo-1-phenyl-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(1-tert-butyl-2-methyl-1H-pyrrol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-2-methyl-1H-pyrrol-3-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-tert-butylfuran-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(2-tert-butyloxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-cyclohexyl-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-((1R,2R)-2-methylcyclohexyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-((1S,2S)-2-methylcyclohexyl)urea,1-cyclohexyl-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(bicyclo[2.2.1]heptan-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-cyclopropyl-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-cyclohexyl-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-cyclohexyl-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(tetrahydrofuran-3-yl)-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(pyrrolidin-3-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(piperidin-4-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(tetrahydrofuran-3-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(3-hydroxycyclopentyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(3-fluorophenyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(2-fluoro-5-(1-(3-fluorophenyl)-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(7-(1,3-dimethyl-1H-pyrazol-5-ylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-(7-(1,3-dimethyl-1H-pyrazol-5-ylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,and salts thereof.
 109. The method of claim 106 wherein said compound isselected from the group consisting of1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(naphthalen-1-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea,and salts thereof.
 110. The method of claim 106 wherein said compound isselected from the group consisting of1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,and salts thereof.
 111. A method of treating an individual sufferingfrom chronic myelogenous leukemia, acute lymphocytic leukemia,gastrointestinal stromal tumors, hypereosinophillic syndrome,glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lungcancers, breast cancers, kidney cancers, cervical carcinomas, metastasisof primary solid tumor secondary sites, ocular diseases characterized byhyperproliferation leading to blindness including various retinopathiesincluding diabetic retinopathy and age-related macular degeneration,rheumatoid arthritis, melanomas, colon cancer, thyroid cancer, a diseasecaused by a mutation in the RAS-RAF-MEK-ERK-MAP kinase pathway, humaninflammation, rheumatoid spondylitis, ostero-arthritis, asthma, goutyarthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis,toxic shock syndrome, adult respiratory distress syndrome, stroke,reperfusion injury, neural trauma, neural ischemia, psoriasis,restenosis, chronic obstructive pulmonary disease, bone resorptivediseases, graft-versus-host reaction, Chron's disease, ulcerativecolitis, inflammatory bowel disease, pyresis, and combinations thereof,comprising the step of administering to such individual a compound ofthe formula Ia′ or IIa′

wherein X—Y is N—CH2; X2 is a direct bond; E1 is phenyl; Q1 is N and Q2is CR3; A is selected from the group consisting of phenyl, naphthyl,C3-C8carbocyclyl, bicycloheptanyl, bicycloheptenyl, and G1; G1 is aheteroaryl taken from the group consisting of pyrrolyl, furyl, thienyl,oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl,oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl,pyridazinyl, triazinyl, pyridinyl, and pyrimidinyl; the A ring may beoptionally substituted with one or more —X1-A1 moieties; X1 is selectedfrom the group consisting of —(CH₂)_(n)—(O)_(r)—(CH₂)_(n)—,—(CH₂)_(n)—(NR3)_(r)-(CH₂)_(n)—, —(CH₂)_(n)—(S)_(r)—(CH₂)_(n)—,—(CH₂)_(n)—(C═O)_(r)—(CH₂)_(n)—, —(CH₂)_(n)—(C(═O)—NR3)_(r)-(CH₂)_(n)—,and —(CH₂)_(n)—(SO₂—NR3)_(r)-(CH₂)_(n)—, wherein any of the alkylenesmay be straight or branched chain; A1 is selected from the groupconsisting of hydrogen, aryl, G1, C1-C6 alkyl, branched C3-C8alkyl, R19substituted C3-C8carbocyclyl, fluoroC1-C6alkyl wherein the alkyl isfully or partially fluorinated, halogen, cyano, hydroxyl, —N(R4)₂, —R5,—C(O)N(R4)₂, C(O)R5, C1-C6alkoxy, and fluoroC1-C6alkoxy wherein thealkyl group is fully or partially fluorinated; when A and A1 have one ormore substitutable sp2-hybridized carbon atom, each respective sp2hybridized carbon atom may be optionally substituted with a Z1 or Z3substituent; when A and A1 have one or more substitutable sp3-hybridizedcarbon atom, each respective sp3 hybridized carbon atom may beoptionally substituted with a Z2 or R3 substituent; when A and A1 haveone or more substitutable nitrogen atom, each respective nitrogen atommay be optionally substituted with a Z4 substituent; each Z1 isindependently and individually selected from the group consisting ofhydrogen, hydroxyC1-C6alkyl, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl,(R4)₂NC1-C6alkyl, (R4)₂NC2-C6alkylN(R4)-(CH₂)_(n),(R4)₂NC2-C6alkylO—(CH₂)_(n), (R3)₂N—C(═O)—, (R4)₂N—C(═O)—,(R4)₂N—CO—C1-C6alkyl-, C1-C6alkoxycarbonyl-, -carboxyC1-C6alkyl,C1-C6alkoxycarbonylC1-C6alkyl, (R3)₂NSO₂—, —SOR3, (R4)₂NSO₂—, —SO₂R3,—SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, —(CH₂)_(n)N(R4)C(O)R8,—(CH₂)_(n)-G1, —(CH₂)_(n)-G4, phenoxy, —(CH₂)_(n)—O—(CH₂)_(n)-G1,—(CH₂)_(n)—O—(CH₂)_(n)-G4, —(CH₂)_(n)—NR3-(CH₂)_(n)-aryl,—(CH₂)_(n)—NR3-(CH₂)_(n)-G1, —(CH₂)_(n)—NR3-(CH₂)_(n)-G4, —S(O)₂R5,—N═S(O)R6R8, —S(O)(═NR3)R6, —(CH₂)_(n)NHC(O)NHS(O)₂R8,—(CH₂)_(n)NHS(O)₂NHC(O)R8, —C(O)NHS(O)₂R8, —S(O)₂NHC(O)R8,—(CH₂)_(n)NHC(O)(CH₂)_(n)R5, —(CH₂)_(n)NHS(O)₂ (CH₂)_(n)R5,—(CH₂)_(n)C(O)NH(CH₂)_(q)R5, —(CH₂)_(n)C(O)R5, —(CH₂)_(n)OC(O)R5,—(CH₂)_(n)S(O)₂NH(CH₂)_(q)R5, —CH(OH)(CH₂)_(p)R5, —CH(OH)CH(OH)R4,—(CH₂)_(n)N(R4)₂, —(CH₂)_(n)R5, —C(═NH)R5, —C(═NH)N(R4)₂, —C(═NOR3)R5,—C(═NOR3)N(R4)₂, and —NHC(═NH)R8; in the event that Z1 contains an alkylor alkylene moiety, such moieties may be further substituted with one ormore C1-C6alkyls; each Z2 is independently and individually selectedfrom the group consisting of hydrogen, aryl, C1-C6alkyl,C3-C8carbocyclyl, hydroxyl, hydroxyC1-C6alkyl-, cyano, (R3)₂N—, (R4)₂N—,(R4)₂NC1-C6alkyl-, (R4)₂NC2-C6alkylN(R4)-(CH₂)_(n)—,(R4)₂NC2-C6alkylO—(CH₂)_(n)—, (R3)₂N—C(═O)—, (R4)₂N—C(═O)—,(R4)₂N—CO—C1-C6alkyl-, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl,C1-C6alkoxycarbonylC1-C6alkyl, (R3)₂NSO₂—, (R4)₂NSO₂—, —SO₂R5, —SO₂R8,—(CH₂)_(n)N(R4)C(O)R8, —C(O)R8, ═O═NOH, ═N(OR6), —(CH₂)_(n)-G1,—(CH₂)_(n)-G4, —(CH₂)_(n)—O—(CH₂)_(n)-G1, —(CH₂)_(n)—O—(CH₂)_(n)-G4,—(CH₂)_(n)—NR3-(CH₂)_(n)-aryl, —(CH₂)_(n)—NR3-(CH₂)_(n)-G1,—(CH₂)_(n)—NR3-(CH₂)_(n)-G4, —(CH₂)_(n)NHC(O)NHS(O)₂R8,—(CH₂)_(n)NHS(O)₂NHC(O)R8, —C(O)NHS(O)₂R8, —(CH₂)NHC(O)(CH₂)_(n)R5,—(CH₂)_(n)NHS(O)₂R5, —(CH₂)_(n)C(O)NH(CH₂)_(q)R5, —(CH₂)_(n)C(O)R5,—(CH₂)_(n)OC(O)R5, and —(CH₂)_(n)R5; in the event that Z2 contains analkyl or alkylene moiety, such moieties may be further substituted withone or more C1-C6alkyls; each Z3 is independently and individuallyselected from the group consisting of H, C1-C6alkyl, branchedC3-C7alkyl, C3-C8carbocyclyl, halogen, fluoroalkyl wherein the alkylmoiety can be partially or fully fluorinated, cyano, hydroxyl, methoxy,oxo, (R3)₂N—C(═O)—, (R4)₂N—C(═O)—, —N(R4)-C(═O)R8, (R3)₂NSO₂—,(R4)₂NSO₂—, —N(R4)SO₂R5, —N(R4)SO₂R8, —(CH₂)_(n)—N(R3)₂,—(CH₂)_(n)—N(R4)₂, —O—(CH₂)_(q)—N(R4)₂, —O—(CH₂)_(q)—O-alkyl,—N(R3)-(CH₂)_(q)—O-alkyl, —N(R3)-(CH₂)_(q)—N(R4)₂, —O—(CH₂)_(q)—R5,—N(R3)-(CH₂)_(q)—R5, —C(═O)R5, —C(═O)R8, and nitro; in the event that Z3contains an alkyl or alkylene moiety, such moieties may be furthersubstituted with one or more C1-C6alkyls; each Z4 is independently andindividually selected from the group consisting of H, C1-C6alkyl,hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4)₂N—C2-C6alkyl,(R4)₂N—C2-C6alkylN(R4)-C2-C6alkyl, (R4)₂N—C2-C6alkyl-O—C2-C6alkyl,(R4)₂N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl,—C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO₂R8, —COR8, —(CH₂)_(n)-G1,—(CH₂)_(n)-G4, —(CH₂)_(q)—O—(CH₂)_(n)-G1, —(CH₂)_(q)—O—(CH₂)_(n)-G4,—(CH₂)_(q)—NR3-(CH₂)_(n)-G1, —(CH₂)_(q)—NR3-(CH₂)_(n)-G4,—(CH₂)_(q)NHC(O)(CH₂)_(n)R5, —(CH₂)_(q)C(O)NH(CH₂)_(q)R5,—(CH₂)_(q)C(O)R5, —(CH₂)_(q)OC(O)R5, —(CH₂)_(q)R5,—(CH₂)_(q)NR4(CH₂)_(q)R5, and —(CH₂)_(q)—O(CH₂)_(q)R5; in the event thatZ4 contains an alkyl or alkylene moiety, such moieties may be furthersubstituted with one or more C1-C6alkyls; each Z6 is independently andindividually selected from the group consisting of H, C1-C6alkyl,branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, —OR4, C1-C6alkylthio,(R3)₂N—, (R4)₂N—, —R5, —N(R3)COR8, —N(R4)COR8, —N(R3)SO₂R6-, —CON(R3)₂,—CON(R4)₂, —COR5, —SO₂N(R4)₂, halogen, fluoroC1-C6alkyl wherein thealkyl is fully or partially fluorinated, cyano, fluoroC1-C6alkoxywherein the alkyl is fully or partially fluorinated,—O—(CH₂)_(q)—N(R4)₂, —N(R3)-(CH₂)_(q)—N(R4)₂, —O—(CH₂)_(q)—O-alkyl,—N(R3)-(CH₂)_(q)—O-alkyl, —O—(CH₂)_(q)—R5, —N(R3)-(CH₂)_(q)—R5,—(NR3)_(r)-(CH₂)_(n)—R17, —(O)_(r)—R17, —(S)_(r)—R17, and—(CH₂)_(r)—R17; in the event that Z6 contains an alkyl or alkylenemoiety, such moieties may be further substituted with one or moreC1-C6alkyls; wherein each R3 is independently and individually selectedfrom the group consisting of H, C1-C6alkyl, branched C3-C7alkyl,C3-C8carbocyclyl, and Z3-substituted phenyl; each R4 is independentlyand individually selected from the group consisting of H, C1-C6alkyl,hydroxyC1-C6alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branchedC3-C7alkyl, branched hydroxyC1-C6alkyl, branched C1-C6alkoxyC1-C6alkyl,branched dihydroxyC1-C6alkyl, —(CH₂)—N(R7)₂, —(CH₂)—R5,—(CH₂)—C(O)N(R7)₂, —(CH₂)_(n)C(O)R5, —(CH₂)_(n)—C(O)OR3,C3-C8carbocyclyl, hydroxyl substituted C3-C8carbocyclyl, alkoxysubstituted C3-C8carbocyclyl, dihydroxy substituted C3-C8carbocyclyl,and —(CH₂)_(n)—R17; each R5 is independently and individually selectedfrom the group consisting of

and wherein the symbol (##) is the point of attachment of the R5 moiety;each R6 is independently and individually selected from the groupconsisting of C1-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, phenyl,and G1; each R7 is independently and individually selected from thegroup consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl,dihydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, branched C3-C7alkyl,branched hydroxyC2-C6 alkyl, branched C1-C6alkoxyC2-C6alkyl, brancheddihydroxyC2-C6alkyl, —(CH₂)_(q)—R5, —(CH₂)_(n)—C(O)R5,—(CH₂)_(n)—C(O)OR3, C3-C8carbocyclyl, hydroxyl substitutedC3-C8carbocyclyl, alkoxy substituted C3-C8carbocyclyl, dihydroxysubstituted C3-C8carbocyclyl, and —(CH₂)_(n)—R17; each R8 isindependently and individually selected from the group consisting ofC1-C6alkyl, branched C3-C7alkyl, fluoroalkyl wherein the alkyl moiety ispartially or fully fluorinated, C3-C8carbocyclyl, Z3-substituted phenyl,Z3-substituted phenyl C1-C6alkyl, Z3-substituted G1, Z3-substitutedG1-C1-C6alkyl, OH, C1-C6alkoxy, N(R3)₂, N(R4)₂, and R5; each R10 isindependently and individually selected from the group consisting ofCO₂H, CO₂C1-C6alkyl, CO—N(R4)₂, OH, C1-C6alkoxy, and —N(R4)₂; R16 isindependently and individually selected from the group consisting ofhydrogen, C1-C6alkyl, and halogen; each R17 is taken from the groupcomprising phenyl, naphthyl, pyrrolyl, furyl, thienyl, oxazolyl,thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl,oxetanyl, azetadinyl, tetrahydrofuranyl, oxazolinyl, oxazolidinyl,pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, azepinyl, oxepinyl,diazepinyl, pyrrolidinyl, and piperidinyl; wherein R17 can be furthersubstituted with one or more Z2, Z3 or Z4 moieties; R19 is H or C1-C6alkyl; wherein two R3 or R4 moieties are independently and individuallytaken from the group consisting of C1-C6alkyl and branched C3-C6alkyl,hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogenatom, said moieties may cyclize to form a C3-C7 heterocyclyl ring; and kis 1 or 2; n is 0-6; p is 1-4; q is 2-6; r is 0 or 1; t is 1-3, andsalts thereof.
 112. The method of claim 111 wherein said compound isselected from the group consisting of1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-t-butyl-1-phenyl-1H-pyrazol-5-yl)urea,1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-t-butyl-1-methyl-1H-pyrazol-5-yl)urea,1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea,1-(3-tert-butylphenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea,1-(3-t-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea,1-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea,1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea,1-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(naphthalen-1-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea,1-(2-tert-butyl-4-(piperazin-1-yl)pyrimidin-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-cyclohexyl-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-cyclohexyl-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-cyclohexyl-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(1-tert-butyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butylisoxazol-5-yl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea,and salts thereof.
 113. The method of claim 111 wherein said compound isselected from the group consisting of1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)urea,1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)urea,1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2,4-difluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2,4-difluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-chloroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-chloroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-tert-butyl-4-chloroisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(1-tert-butyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-imidazol-4-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(1-tert-butyl-1H-imidazol-4-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-2-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-2-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-pyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea,1-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-tert-butylthiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-tert-butyl-3-methylthiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-tert-butyl-3-chlorothiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-tert-butyl-3-fluorothiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-tert-butylisoxazol-5-yl)urea,1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butylisoxazol-5-yl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2,4-difluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2,4-difluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2,4-difluoro-5-(7-(methylamino)-2-oxo-1-phenyl-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2,4-difluoro-5-(7-(methylamino)-2-oxo-1-phenyl-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(1-tert-butyl-2-methyl-1H-pyrrol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-2-methyl-1H-pyrrol-3-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-tert-butylfuran-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(2-tert-butyloxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-cyclohexyl-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-((1R,2R)-2-methylcyclohexyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-((1S,2S)-2-methylcyclohexyl)urea,1-cyclohexyl-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(bicyclo[2.2.1]heptan-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-cyclopropyl-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-cyclohexyl-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-cyclohexyl-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(tetrahydrofuran-3-yl)-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(pyrrolidin-3-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(piperidin-4-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(tetrahydrofuran-3-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(3-hydroxycyclopentyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(3-fluorophenyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(2-fluoro-5-(1-(3-fluorophenyl)-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(7-(1,3-dimethyl-1H-pyrazol-5-ylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-(7-(1,3-dimethyl-1H-pyrazol-5-ylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,and salts thereof.
 114. The method of claim 111 wherein said compound isselected from the group consisting of1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(naphthalen-1-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea,and salts thereof.
 115. The method of claim 111 wherein said compound isselected from the group consisting of1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,and salts thereof.
 116. A method of administering to a mammal a compoundof the formula Ia′ or IIa′

wherein X—Y is N—CH2; X2 is a direct bond; E1 is phenyl; Q1 is N and Q2is CR3; A is selected from the group consisting of phenyl, naphthyl,C3-C8carbocyclyl, bicycloheptanyl, bicycloheptenyl, and G1; G1 is aheteroaryl taken from the group consisting of pyrrolyl, furyl, thienyl,oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl,oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl,pyridazinyl, triazinyl, pyridinyl, and pyrimidinyl; the A ring may beoptionally substituted with one or more —X1-A1 moieties; X1 is selectedfrom the group consisting of —(CH₂)_(n)—(O)_(r)—(CH₂)_(n)—,—(CH₂)_(n)—(NR3)-(CH₂)_(n)—, —(CH₂)_(n)—(S)_(r)—(CH₂)_(n)—,—(CH₂)_(n)—(C═O)_(r)—(CH₂)_(n)—, —(CH₂)_(n)—(C(═O)—NR3)_(r)-(CH₂)_(n)—,and —(CH₂)_(n)—(SO₂—NR3)_(r)-(CH₂)_(n)—, wherein any of the alkylenesmay be straight or branched chain; A1 is selected from the groupconsisting of hydrogen, aryl, G1, C1-C6 alkyl, branched C3-C8alkyl, R19substituted C3-C8carbocyclyl, fluoroC1-C6alkyl wherein the alkyl isfully or partially fluorinated, halogen, cyano, hydroxyl, —N(R4)₂, —R5,—C(O)N(R4)₂, C(O)R5, C1-C6alkoxy, and fluoroC1-C6alkoxy wherein thealkyl group is fully or partially fluorinated; when A and A1 have one ormore substitutable sp2-hybridized carbon atom, each respective sp2hybridized carbon atom may be optionally substituted with a Z1 or Z3substituent; when A and A1 have one or more substitutable sp3-hybridizedcarbon atom, each respective sp3 hybridized carbon atom may beoptionally substituted with a Z2 or R3 substituent; when A and A1 haveone or more substitutable nitrogen atom, each respective nitrogen atommay be optionally substituted with a Z4 substituent; each Z1 isindependently and individually selected from the group consisting ofhydrogen, hydroxyC1-C6alkyl, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl,(R4)₂NC1-C6alkyl, (R4)₂NC2-C6alkylN(R4)-(CH₂)_(n),(R4)₂NC2-C6alkylO—(CH₂)_(n), (R3)₂N—C(═O)—, (R4)₂N—C(═O)—,(R4)₂N—CO—C1-C6alkyl-, C1-C6alkoxycarbonyl-, -carboxyC1-C6alkyl,C1-C6alkoxycarbonylC1-C6alkyl, (R3)₂NSO₂—, —SOR3, (R4)₂NSO₂—, —SO₂R3,—SOR4, —C(═O)R6, —C(═NOH)R6, —C(═NOR3)R6, —(CH₂)_(n)N(R4)C(O)R8,—(CH₂)_(n)-G1, —(CH₂)_(n)-G4, phenoxy, —(CH₂)_(n)—O—(CH₂)_(n)-G1,—(CH₂)_(n)—O—(CH₂)_(n)-G4, —(CH₂)_(n)—NR3-(CH₂)_(n)-aryl,—(CH₂)_(n)—NR3-(CH₂)_(n)-G1, —(CH₂)_(n)—NR3-(CH₂)_(n)-G4, —S(O)₂R5,—N═S(O)R6R8, —S(O)(═NR3)R6, —(CH₂)_(n)NHC(O)NHS(O)₂R8,—(CH₂)_(n)NHS(O)₂NHC(O)R8, —C(O)NHS(O)₂R8, —S(O)₂NHC(O)R8,—(CH₂)_(n)NHC(O)(CH₂)_(n)R5, —(CH₂)_(n)NHS(O)₂ (CH₂)_(n)R5,—(CH₂)_(n)C(O)NH(CH₂)_(q)R5, —(CH₂)_(n)C(O)R5, —(CH₂)_(n)OC(O)R5,—(CH₂)_(n)S(O)₂NH(CH₂)_(q)R5, —CH(OH)(CH₂)_(p)R5, —CH(OH)CH(OH)R4,—(CH₂)_(n)N(R4)₂, —(CH₂)_(n)R5, —C(═NH)R5, —C(═NH)N(R4)₂, —C(═NOR3)R5,—C(═NOR3)N(R4)₂, and —NHC(═NH)R8; in the event that Z1 contains an alkylor alkylene moiety, such moieties may be further substituted with one ormore C1-C6alkyls; each Z2 is independently and individually selectedfrom the group consisting of hydrogen, aryl, C1-C6alkyl,C3-C8carbocyclyl, hydroxyl, hydroxyC1-C6alkyl-, cyano, (R3)₂N—, (R4)₂N—,(R4)₂NC1-C6alkyl-, (R4)₂NC2-C6alkylN(R4)-(CH₂)_(n)—,(R4)₂NC2-C6alkylO—(CH₂)_(n)—, (R3)₂N—C(═O)—, (R4)₂N—C(═O)—,(R4)₂N—CO—C1-C6alkyl-, carboxyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonyl,C1-C6alkoxycarbonylC1-C6alkyl, (R3)₂NSO₂—, (R4)₂NSO₂—, —SO₂R5, —SO₂R8,—(CH₂)_(n)N(R4)C(O)R8, —C(O)R8, ═O═NOH, ═N(OR6), —(CH₂)_(n)-G1,—(CH₂)_(n)-G4, —(CH₂)_(n)—O—(CH₂)_(n)-G1, —(CH₂)_(n)—O—(CH₂)_(n)-G4,—(CH₂)_(n)—NR3-(CH₂)_(n)-aryl, —(CH₂)_(n)—NR3-(CH₂)_(n)-G1,—(CH₂)_(n)—NR3-(CH₂)_(n)-G4, —(CH₂)_(n)NHC(O)NHS(O)₂R8,—(CH₂)_(n)NHS(O)₂NHC(O)R8, —C(O)NHS(O)₂R8, —(CH₂)NHC(O)(CH₂)_(n)R5,—(CH₂)_(n)NHS(O)₂R5, —(CH₂)_(n)C(O)NH(CH₂)_(q)R5, —(CH₂)_(n)C(O)R5,—(CH₂)_(n)OC(O)R5, and —(CH₂)_(n)R5; in the event that Z2 contains analkyl or alkylene moiety, such moieties may be further substituted withone or more C1-C6alkyls; each Z3 is independently and individuallyselected from the group consisting of H, C1-C6alkyl, branchedC3-C7alkyl, C3-C8carbocyclyl, halogen, fluoroalkyl wherein the alkylmoiety can be partially or fully fluorinated, cyano, hydroxyl, methoxy,oxo, (R3)₂N—C(═O)—, (R4)₂N—C(═O)—, —N(R4)-C(═O)R8, (R3)₂NSO₂—,(R4)₂NSO₂—, —N(R4)SO₂R5, —N(R4)SO₂R8, —(CH₂)_(n)—N(R3)₂,—(CH₂)_(n)—N(R4)₂, —O—(CH₂)_(q)—N(R4)₂, —O—(CH₂)_(q)—O-alkyl,—N(R3)-(CH₂)_(q)—O-alkyl, —N(R3)-(CH₂)_(q)—N(R4)₂, —O—(CH₂)_(q)—R5,—N(R3)-(CH₂)_(q)—R5, —C(═O)R5, —C(═O)R8, and nitro; in the event that Z3contains an alkyl or alkylene moiety, such moieties may be furthersubstituted with one or more C1-C6alkyls; each Z4 is independently andindividually selected from the group consisting of H, C1-C6alkyl,hydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, (R4)₂N—C2-C6alkyl,(R4)₂N—C2-C6alkylN(R4)-C2-C6alkyl, (R4)₂N—C2-C6alkyl-O—C2-C6alkyl,(R4)₂N—CO—C1-C6alkyl, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl,—C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)-, —SO₂R8, —COR8, —(CH₂)_(n)-G1,—(CH₂)_(n)-G4, —(CH₂)_(q)—O—(CH₂)_(n)-G1, —(CH₂)_(q)—O—(CH₂)_(n)-G4,—(CH₂)_(q)—NR3-(CH₂)_(n)-G1, —(CH₂)_(q)—NR3-(CH₂)_(n)-G4,—(CH₂)_(q)NHC(O)(CH₂)_(n)R5, —(CH₂)_(q)C(O)NH(CH₂)_(q)R5,—(CH₂)_(q)C(O)R5, —(CH₂)_(q)OC(O)R5, —(CH₂)_(q)R5,—(CH₂)_(q)NR4(CH₂)_(q)R5, and —(CH₂)_(q)—O(CH₂)_(q)R5; in the event thatZ4 contains an alkyl or alkylene moiety, such moieties may be furthersubstituted with one or more C1-C6alkyls; each Z6 is independently andindividually selected from the group consisting of H, C1-C6alkyl,branched C3-C7alkyl, hydroxyl, C1-C6alkoxy, —OR4, C1-C6alkylthio,(R3)₂N—, (R4)₂N—, —R5, —N(R3)COR8, —N(R4)COR8, —N(R3)SO₂R6-, —CON(R3)₂,—CON(R4)₂, —COR5, —SO₂N(R4)₂, halogen, fluoroC1-C6alkyl wherein thealkyl is fully or partially fluorinated, cyano, fluoroC1-C6alkoxywherein the alkyl is fully or partially fluorinated,—O—(CH₂)_(q)—N(R4)₂, —N(R3)-(CH₂)_(q)—N(R4)₂, —O—(CH₂)_(q)—O-alkyl,—N(R3)-(CH₂)_(q)—O-alkyl, —O—(CH₂)_(q)—R5, —N(R3)-(CH₂)_(q)—R5,—(NR3)_(r)-(CH₂)_(n)—R17, —(O)_(r)—R17, —(S)_(r)—R17, and—(CH₂)_(r)—R17; in the event that Z6 contains an alkyl or alkylenemoiety, such moieties may be further substituted with one or moreC1-C6alkyls; wherein each R3 is independently and individually selectedfrom the group consisting of H, C1-C6alkyl, branched C3-C7alkyl,C3-C8carbocyclyl, and Z3-substituted phenyl; each R4 is independentlyand individually selected from the group consisting of H, C1-C6alkyl,hydroxyC1-C6alkyl, dihydroxyC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, branchedC3-C7alkyl, branched hydroxyC1-C6alkyl, branched C1-C6alkoxyC1-C6alkyl,branched dihydroxyC1-C6alkyl, —(CH₂)_(p)—N(R7)₂, —(CH₂)_(p)—R5,—(CH₂)_(p)—C(O)N(R7)₂, —(CH₂)_(n)C(O)R5, —(CH₂)_(n)—C(O)OR3,C3-C8carbocyclyl, hydroxyl substituted C3-C8carbocyclyl, alkoxysubstituted C3-C8carbocyclyl, dihydroxy substituted C3-C8carbocyclyl,and —(CH₂)_(n)—R17; each R5 is independently and individually selectedfrom the group consisting of

and wherein the symbol (##) is the point of attachment of the R5 moiety;each R6 is independently and individually selected from the groupconsisting of C1-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, phenyl,and G1; each R7 is independently and individually selected from thegroup consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl,dihydroxyC2-C6alkyl, C1-C6alkoxyC2-C6alkyl, branched C3-C7alkyl,branched hydroxyC2-C6 alkyl, branched C1-C6alkoxyC2-C6alkyl, brancheddihydroxyC2-C6alkyl, —(CH₂)_(q)—R5, —(CH₂)_(n)—C(O)R5,—(CH₂)_(n)—C(O)OR3, C3-C8carbocyclyl, hydroxyl substitutedC3-C8carbocyclyl, alkoxy substituted C3-C8carbocyclyl, dihydroxysubstituted C3-C8carbocyclyl, and —(CH₂)_(n)—R17; each R8 isindependently and individually selected from the group consisting ofC1-C6alkyl, branched C3-C7alkyl, fluoroalkyl wherein the alkyl moiety ispartially or fully fluorinated, C3-C8carbocyclyl, Z3-substituted phenyl,Z3-substituted phenyl C1-C6alkyl, Z3-substituted G1, Z3-substitutedG1-C1-C6alkyl, OH, C1-C6alkoxy, N(R3)₂, N(R4)₂, and R5; each R10 isindependently and individually selected from the group consisting ofCO₂H, CO₂C1-C6alkyl, CO—N(R4)₂, OH, C1-C6alkoxy, and —N(R4)₂; R16 isindependently and individually selected from the group consisting ofhydrogen, C1-C6alkyl, and halogen; each R17 is taken from the groupcomprising phenyl, naphthyl, pyrrolyl, furyl, thienyl, oxazolyl,thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl,oxetanyl, azetadinyl, tetrahydrofuranyl, oxazolinyl, oxazolidinyl,pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, azepinyl, oxepinyl,diazepinyl, pyrrolidinyl, and piperidinyl; wherein R17 can be furthersubstituted with one or more Z2, Z3 or Z4 moieties; R19 is H or C1-C6alkyl; wherein two R3 or R4 moieties are independently and individuallytaken from the group consisting of C1-C6alkyl and branched C3-C6alkyl,hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogenatom, said moieties may cyclize to form a C3-C7 heterocyclyl ring; and kis 1 or 2; n is 0-6; p is 1-4; q is 2-6; r is 0 or 1; t is 1-3, andsalts thereof, said method of administration selected from the groupconsisting of oral, parenteral, inhalation, and subcutaneous.
 117. Themethod of claim 116 wherein said compound is selected from the groupconsisting of1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-t-butyl-1-phenyl-1H-pyrazol-5-yl)urea,1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-t-butyl-1-methyl-1H-pyrazol-5-yl)urea,1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea,1-(3-tert-butylphenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea,1-(3-t-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea,1-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea,1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(5-(7-(2-(dimethylamino)ethylamino)-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea,1-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(naphthalen-1-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea,1-(2-tert-butyl-4-(piperazin-1-yl)pyrimidin-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-cyclohexyl-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-cyclohexyl-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-cyclohexyl-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(1-tert-butyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butylisoxazol-5-yl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea,and salts thereof.
 118. The method of claim 116 wherein said compound isselected from the group consisting of1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)urea,1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)urea,1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2,4-difluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2,4-difluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-chloroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-chloroisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-tert-butyl-4-chloroisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(1-tert-butyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-imidazol-4-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(1-tert-butyl-1H-imidazol-4-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-5-methyl-1H-imidazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-2-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-2-methyl-1H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-pyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea,1-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea,1-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-tert-butylthiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-tert-butyl-3-methylthiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-tert-butyl-3-chlorothiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-tert-butyl-3-fluorothiophen-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-5-methyl-1H-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-tert-butylisoxazol-5-yl)urea,1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-tert-butylisoxazol-5-yl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2,4-difluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2,4-difluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2,4-difluoro-5-(7-(methylamino)-2-oxo-1-phenyl-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2,4-difluoro-5-(7-(methylamino)-2-oxo-1-phenyl-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(1-tert-butyl-2-methyl-1H-pyrrol-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-2-methyl-1H-pyrrol-3-yl)-3-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(4-tert-butylfuran-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(2-tert-butyloxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-cyclohexyl-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-((1R,2R)-2-methylcyclohexyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-((1S,2S)-2-methylcyclohexyl)urea,1-cyclohexyl-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(bicyclo[2.2.1]heptan-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-cyclopropyl-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-cyclohexyl-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-cyclohexyl-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(tetrahydrofuran-3-yl)-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(pyrrolidin-3-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(piperidin-4-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(tetrahydrofuran-3-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(7-(methylamino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(3-hydroxycyclopentyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(1-(3-fluorophenyl)-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)urea,1-(2-fluoro-5-(1-(3-fluorophenyl)-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)-3-(3-isopropylisoxazol-5-yl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(7-(1,3-dimethyl-1H-pyrazol-5-ylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-(7-(1,3-dimethyl-1H-pyrazol-5-ylamino)-1-methyl-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,and salts thereof.
 119. The method of claim 116 wherein said compound isselected from the group consisting of1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)-3-(naphthalen-1-yl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea,1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea,and salts thereof.
 120. The method of claim 116 wherein said compound isselected from the group consisting of1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea,1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea,1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea,1-(3-tert-butylisoxazol-5-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluoro-4-methylphenyl)urea,and salts thereof.